CN105814048A - Fused tricyclic imidazole derivatives as modulators of TNF activity - Google Patents

Fused tricyclic imidazole derivatives as modulators of TNF activity Download PDF

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CN105814048A
CN105814048A CN201480067052.9A CN201480067052A CN105814048A CN 105814048 A CN105814048 A CN 105814048A CN 201480067052 A CN201480067052 A CN 201480067052A CN 105814048 A CN105814048 A CN 105814048A
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base
amino
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CN105814048B (en
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R·P·亚历山大
M·D·卡尔米安诺
S·德菲斯
V·迪里厄
M·戴里格尼
J·P·希尔
V·E·杰克逊
J·凯耶尔特斯
B·克罗普里恩
M·马克考斯
Y·A·萨布尼斯
M·D·赛尔比
D·L·L·斯温南
N·范霍特温
朱昭宁
U·海内尔特
V·魏纳
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UCB Pharma SA
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

A series of fused tricyclic imidazole derivatives, in particular dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridine derivatives, and analogues thereof, being potent modulators of human TNF alpha activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

Description

Fused tricyclic benzimidizole derivatives as TNF active regulator
The present invention relates to a class fused tricyclic benzimidizole derivatives and they purposes in the treatment.More specifically, this Invention relates to the most activated benzimidizole derivatives condensed being replaced.In particular it relates to dihydro- 1H-imidazo [1,2-a] benzimidazole, dihydro-1H-pyrrolo-[1,2-a] benzimidazole, dihydro-1H-pyrazine also [1,2-a] Benzimidazole, dihydro-1H-[1,4]Piperazine also [4,3-a] benzimidazole and thiazoline also [3,4-a] benzimidazole.
These compounds are the regulators of the signal conduction of TNF α, are therefore useful as medical substance, especially exist Disadvantageous struvite and autoimmune disorders, neurological and neural degeneration obstacle, pain and nociception sexual disorders, cardiovascular In the treatment of obstacle, dysbolismus, eye disorder and oncology's obstacle.
TNF α is tumor necrosis factor (TNF) super families of the major function of total regulation cell survival and cell death The prototypical member of protein.The architectural feature that all known member of TNF superfamily has is to combine and activate specific The formation of the trimer compositions of TNF superfamily receptors.As an example, TNF α exists with solvable and cross-film form, and passes through quilt Be referred to as TNFR1 and TNFR2, two kinds of receptors with unique function end points signal.
The multiple product that can regulate TNF α activity is obtained commercially.Above-mentioned being the most approved for treats inflammation Disease property and autoimmune disorders such as rheumatoid arthritis and Crohn disease.The most all the product of approval is macromole , and worked by suppression human TNF alpha and the combination of its receptor.Typical macromole TNF α inhibitor includes that anti-TNF alpha resists Body；With soluble TNFot receptor fusion protein.The example of the Anti-tnfa antibody being obtained commercially includes human antibody such as A Da wood Monoclonal antibodyWith dagger-axe profit wood monoclonal antibodyChimeric antibody such as infliximab With Fab ' fragment such as training house pearl monoclonal antibody (certolizumab pegol) of PegylationIt is obtained commercially An example of soluble TNFot receptor fusion protein be Embrel
TNF superfamily member (including TNF α itself) involves multiple being considered and has the disease of notable medical importance at some The physiology and the pathology function that play a role in disease (see, e.g., M.G.Tansey and D.E.Szymkowski, Drug Discovery Today,2009,14,1082-1088；With F.S.Carneiro et al., J.Sexual Medicine, 2010, 7,3823-3834)。
Compound according to the present invention be human TNF alpha activity effective regulator, therefore multiple human disease treatment and/ Or prevention is useful.These include autoimmune and struvite obstacle；Neurological and neural degeneration obstacle；Pain and injury Susceptibility obstacle；Cardiovascular disorder；Dysbolismus；Eye disorder；With oncology's obstacle.
It addition, can be useful according to the compound of the present invention as pharmacologic criteria, described pharmacologic criteria be used for The pharmacological agents that exploitation new biological tests is new with searching.Thus, in one embodiment, the compound of the present invention is permissible It is used in the mensuration of detection pharmacologically active chemical compounds as radioligand.In an alternative embodiment, the present invention Some compound may be used for being coupled to fluorogen to provide fluorophore conjugate, and described fluorophore conjugate can be used in for detecting In the mensuration (such as fluorescence polarization determination) of pharmacologically active chemical compounds.
The international patent application WO 2013/186229 (December in 2013 disclosure on the 19th) of CO-PENDING, WO 2014/ 009295 (on January 16th, 2014 is open) and WO 2014/009296 (also open on January 16th, 2014) describe as people The condensed imidazole derivatives of TNF α active regulator.
But, the most available prior art is the openest or the prompting present invention provides condenses benzimidazole The precision architecture classification of derivant.When test in fluorescence polarization determination described herein, according to the compound of the present invention Fluorophotometry conjugate and the combination of TNF α effectively.It practice, when test in this mensuration, the compound performance of the present invention Go out 50 μMs or less, usual 20 μMs or less, often 5 μMs or less, typically 1 μM or less, suitably 500nM or less, 100nM or the less and IC of preferably 20nM or less ideally50Value (skilled person will understand that, the lowest IC50Numeral represents The most activated compound).
Some compound according to the present invention is being referred to as HEK-BlueTMThe HEK-293 being obtained commercially of CD40L derives Reporting cell line neutralizes the activity of TNF α effectively.This is at the IFN β minimal promoter being fused to 5 NF-κ B binding sites The cell line that transfects of the stable HEK-293 controlling lower expression SEAP (embryonic alkaline phosphatase of secretion).These cells SEAP is secreted and is stimulated in the way of concentration dependent by TNF α.When (the most also being claimed in HEK-293 bioassay Make reports genetic testing) in test time, some compound of the present invention shows 50 μMs or 20 μMs or less, warp less, usual Normal 5 μMs or less, typically 1 μM or less, suitably 500nM or less, ideally 100nM or less and preferably 20nM or Less IC50Value (as before, skilled person will understand that, the lowest IC50Numeral represents the most activated compound).
The invention provides the compound of formula (I) or its N-oxide or its pharmaceutically acceptable salt or solvation Thing or its glucuronide or its eutectic:
Wherein
N represents the integer equal to 0 or 1；
X and Z represents covalent bond independently；Or hetero atom；Or carbonyl, or S (O)-,-S (O)2-、-S(O)(N-Rd)、-NC (O)-Rd、-N(CO)-ORd、-NS(O)2RdOr-N (Rd)；Or the straight or branched C being optionally substituted1-4Alkylidene chain；
Y represents C3-7Cycloalkyl, aryl, C3-7Heterocyclylalkyl or heteroaryl, any one in described group can be optionally It is substituted with one or more substituents；
R1And R2Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy ,-OR independentlya、-SRa、- SORa、-SO2Ra、-SF5、-NRbRc、-NRcCORd、-NRcCO2Rd、-NHCONRbRc、-NRcSO2Re、-N(SO2Re)2、- NHSO2NRbRc、-CORd、-CO2Rd、-CONRbRc、-CON(ORa)Rb、-SO2NRbRcOr-S (O) (N-Rd)Ra；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C3-7Cycloalkyl, C4-7Cycloalkenyl group, C3-7Cycloalkyl (C1-6) alkyl, aryl, aryl (C1-6) alkyl, C3-7 Heterocyclylalkyl, C3-7Heterocyclylalkyl (C1-6) alkyl, C3-7Heterocycloalkenyl, C4-9Miscellaneous bicyclic alkyl, heteroaryl, heteroaryl (C1-6) alkane Base, (C3-7) Heterocyclylalkyl (C1-6) alkyl-aryl-group-, heteroaryl (C3-7) Heterocyclylalkyl-, (C3-7) cycloalkyl-heteroaryl-, (C3-7) cycloalkyl (C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl-heteroaryl-, (C3-7) Heterocyclylalkyl-heteroaryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-heteroaryl-, (C4-9) miscellaneous Bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl-, any one in described group can be optionally by one Or multiple substituent group replaces；
R3And R4Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy independently；Or-ORa、- SRa、-SORaOr-SO2Ra；Or the C being optionally substituted with one or more substituents1-6Alkyl.
R5aAnd R5bRepresent hydrogen, hydroxyl, halogen, trifluoromethyl or cyano group independently；Or-NRbRc、-NRcC(O)Rd、-(CO) NRcRd、-NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)Ra、-S(O)2(N-Rd)、-ORd、-C(O)-ORd Or-O (CO)-Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heteroaryl, any one in described group can be appointed Selection of land is substituted with one or more substituents；Or R5aAnd R5bCarbonyl, thiocarbonyl is represented together with the carbon being connected with them Or-C=N-OH (thiocarbonyl)；And
R6Represent hydrogen, hydroxyl, halogen, trifluoromethyl or cyano group；Or-NRbRc、-NRcC(O)Rd、-(CO)NRcRd、-NHS (O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)Ra、-S(O)2(N-Rd)、-ORd、-C(O)-ORdOr-O (CO)- Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heteroaryl, any one in described group can be optionally by one Or multiple substituent group replaces；Or R6Formed together with the carbon being connected with them with Y and be optionally substituted with one or more substituents C3-7Cycloalkyl or C3-7Heterocyclylalkyl；And
RaRepresent C1-6Alkyl, C3-7Cycloalkyl, C3-7Heterocyclylalkyl, aryl, aryl (C1-6) alkyl, heteroaryl or heteroaryl (C1-6) alkyl, any one in described group can optionally be substituted with one or more substituents；
RbAnd RcRepresent hydrogen or trifluoromethyl independently；Or C1-6Alkyl, C3-7Cycloalkyl, C3-7Cycloalkyl (C1-6) alkyl, virtue Base, aryl (C1-6) alkyl, C3-7Heterocyclylalkyl, C3-7Heterocyclylalkyl (C1-6) alkyl, heteroaryl or heteroaryl (C1-6) alkyl, institute State any one in group can optionally be substituted with one or more substituents；Or
RbAnd RcRepresent together with the nitrogen-atoms being connected with both of which azetidine-1-base, pyrrolidin-1-yl, Oxazolidine-3-base, differentOxazolidine-2-base, Thiazolidine-3-base, isothiazolidine-2-base, piperidin-1-yl, morpholine-4-base, sulfur generation Quinoline (thiomorpholin)-4-base, piperazine-1-base, high piperidin-1-yl, high morpholine-4-base, homopiperazine-1-base, (imino group) (oxo) thiazan (thiazinan)-4-base, (oxo) thiazan-4-base or (dioxo) thiazan-4-base, described group In any one can optionally be substituted with one or more substituents；
RdRepresent hydrogen；Or C1-6Alkyl, C3-7Cycloalkyl, aryl, C3-7Heterocyclylalkyl or heteroaryl, appointing in described group One can optionally be substituted with one or more substituents；And
ReRepresent C1-6Alkyl, aryl or heteroaryl, any one in described group can optionally be taken by one or more Replace for base.
Present invention also offers the compound by formula as defined above (I) in the treatment or its N-oxide or its medicine Acceptable salt or solvate or its glucuronide or its eutectic on.
Present invention also offers obstacle as above fixed being instructed to use TNF α function regulator for treatment and/or prevention The compound of formula (I) of justice or its N-oxide or its pharmaceutically acceptable salt or solvate or its glucosiduronic acid spread out Biology or its eutectic.
In yet another aspect, the invention provides the compound of formula as defined above (I) or its N-oxide or its medicine On, acceptable salt is for preparing the purposes of medicine, and described medicine can be used for treating struvite or autoimmune disorders, god The study of Confucian classics or neural degeneration obstacle, pain or nociception sexual disorders, cardiovascular disorder, dysbolismus, eye disorder or oncology's barrier Hinder.
In yet another aspect, present invention provide for treatment and/or preventing inflammatory or autoimmune disorders, nerve Learn or neural degeneration obstacle, pain or nociception sexual disorders, cardiovascular disorder, dysbolismus, eye disorder or oncology's obstacle The compound of formula as defined above (I) or its N-oxide or its pharmaceutically acceptable salt or solvate or its Portugal Glycuronide derivant or its eutectic.
Present invention also offers a kind of side being instructed to use the obstacle of TNF α function regulator for treatment and/or prevention Method, described method includes compound or its N-using the formula as defined above (I) of effective dose to the patient of this treatment of needs Oxide or its pharmaceutically acceptable salt or solvate or its glucuronide or its eutectic.
In yet another aspect, the invention provides a kind of for treatment and/or preventing inflammatory or autoimmune disorders, Neurological or neural degeneration obstacle, pain or nociception sexual disorders, cardiovascular disorder, dysbolismus, eye disorder or oncology The method of obstacle, described method includes the chemical combination using the formula as defined above (I) of effective dose to the patient of this treatment of needs Thing or its N-oxide or its pharmaceutically acceptable salt or solvate or its glucuronide or its eutectic.
When any group in the compound of above formula (I) is said into optionally replace time, this group can be not taken Generation, or be substituted with one or more substituents.Typically, this type of group is unsubstituted, or is taken by one or two Replace for base.
For medicinal, the salt of the compound of formula (I) will be pharmaceutically acceptable salt.But, other salt can be used for making The standby compound used in the present invention or their pharmaceutically acceptable salt.As selecting and preparing pharmaceutically acceptable The standard guidelines on the basis of salt is described in, such as, and Handbook of Pharmaceutical Salts:Properties, Selection and Use, P.H.Stahl and C.G.Wermuth compile, Wiley-VCH, and 2002.The change used in the present invention The suitable pharmaceutically acceptable salt of compound includes acid-addition salts, and it can be formed the most as follows: will be used in the present invention Solution and pharmaceutically acceptable acid (all example hydrochloric acids, sulphuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, the second of compound Acid, benzoic acid, citric acid, tartaric acid or phosphoric acid) solution mixing.Additionally, the compound that ought use in the present invention carries acid During property part (such as carboxyl), its suitable pharmaceutically acceptable salt can include alkali metal salt, such as sodium or potassium salt；Alkaline earth Slaine, such as calcium or magnesium salt；Ammonium salt；With the salt formed with suitable organic ligand, such as quaternary ammonium salt and meglumine salt.
The present invention includes the solvate of the compound of above formula (I) in the range of it.Such solvate is permissible Formed with following solvent: ordinary organic solvents, such as hydrocarbon solvent such as benzene or toluene；The solvent of chlorination such as chloroform or dichloromethane Alkane；Alcoholic solvent such as methanol, ethanol or isopropanol；Ether solvents such as ether or oxolane；Or ester solvent such as ethyl acetate. Alternatively, the solvate of the compound of formula (I) can be formed with water, and in this case, they will be hydrate.
The present invention also includes eutectic in the range of it.Technical term " eutectic " is used for describing such situation: Qi Zhongzhong Property molecular components is present in crystalline compounds with clear and definite stoichiometric proportion.The preparation of medicinal eutectic makes it possible to active drug The crystal formation of thing composition makes a change, and this can change again its physical chemistry in the case of not damaging its expectation biological activity Character (sees Pharmaceutical Salts and Co-crystals, J.Wouters and L.Quere to compile, RSC Publishing,2012).The exemplary of the eutectic forming agent that can be present in together with active pharmaceutical ingredient in eutectic includes L-AA, citric acid, 1,3-propanedicarboxylic acid, urea and nicotiamide.
The present invention includes the prodrug of the compound of above formula (I) in the range of it.It is said that in general, such prodrug will be The functional deriv of the compound of formula (I), it can change into the compound of required formula (I) the most in vivo.Select and system The conventional method of standby suitable prodrug derivant is described in, and such as, Design of Prodrugs, H.Bundgaard compile, Elsevier,1985。
May reside in the suitable alkyl on the compound used in the present invention and include straight chain and side chain C1-6Alkyl, Such as C1-4Alkyl.Exemplary includes methyl and ethyl, and straight or branched propyl group, butyl and amyl group.Concrete alkyl includes Methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, 2,2-dimethyl propyl and 3-methyl fourth Base.The expression derived such as " C1-6Alkoxyl ", " C1-6Alkylthio group ", " C1-6Alkyl sulphonyl " and " C1-6Alkyl amino " need Correspondingly explain.
Statement " C1-4Alkylidene chain " represent the divalent straight containing 1-4 carbon atom or branched alkylidene chain.Exemplary Including methylene, ethylidene, methylmethylene, ethyl methylene and dimethylated methylene base.
Suitably C2-6Thiazolinyl includes vinyl and pi-allyl.
Suitably C2-6Alkynyl includes acetenyl, propargyl and butynyl.
Term " C used herein3-7Cycloalkyl " represent the list of 3-7 carbon atom derived from saturated monocyclic hydrocarbon Valency group, and its benzo-fused analog can be included.Suitably C3-7(it can comprise the class that it is benzo-fused to cycloalkyl Like thing) include cyclopropyl, cyclobutyl, benzocyclobutane thiazolinyl, cyclopenta, indanyl, cyclohexyl and suberyl.
Term " C used herein4-7Cycloalkenyl group " represent that 4-7 the carbon derived from part unsaturated monocyclic hydrocarbon is former The monoradical of son.Suitably C4-7Cycloalkenyl group includes cyclobutane base, cyclopentenyl, cyclohexenyl group and cycloheptenyl.
Term " C used herein4-9Bicyclic alkyl " represent 4-9 carbon atom deriving from saturated bicyclic hydrocarbon Monoradical.Typical bicyclic alkyl includes that bicyclo-[3.1.0] hexyl, bicyclo-[4.1.0] heptane base, bicyclo-[2.2.2] are pungent Alkyl and bicyclo-[3.2.2]-nonyl.
Term " aryl " used herein represents the list that the aromatic ring from single aromatic ring or multiple condensation derives Valency carbocyclic aromatic radical.Suitably aryl includes phenyl and naphthyl, preferably phenyl.
Suitably aryl (C1-6) alkyl includes benzyl, phenylethyl, phenyl propyl and naphthyl methyl.
Term " C used herein3-7Heterocyclylalkyl " represent and contain 3-7 carbon atom with at least one selected from oxygen, sulfur With the heteroatomic saturated monocycle of nitrogen, and its benzo-fused analog can be included.Suitably Heterocyclylalkyl includes oxa-ring Butyl, azelidinyl, tetrahydrofuran base, dihydrobenzo-furyl, dihydrobenzo thienyl, pyrrolidinyl, indoline base, Xylylenimine quinoline base, isoindoline base,Oxazolidinyl, thiazolidinyl, isothiazole alkyl, imidazolidinyl, THP trtrahydropyranyl, Chromanyl, tetrahydrothiopyran base, piperidyl, 1,2,3,4-tetrahydric quinoline group, 1,2,3,4-tetrahydro isoquinolyl, piperazinyl, 1,2, 3,4-tetrahydroquinoxaline base, hexahydro-[1,2,5] thiadiazoles also [2,3-a] pyrazinyl, homopiperazine base, morpholinyl, benzoPiperazine Base, thio-morpholinyl, azacycloheptyl, oxaza heptyl, diazacyclo heptyl, thia diazacyclo heptyl, azacyclo-are pungent Alkyl (azocanyl), (imino group) (oxo) thiazine alkyl (thiazinanyl), (oxo) thiazine alkyl and (dioxo) thiophene Piperazine alkyl.
Term " C used herein3-7Heterocycloalkenyl " represent and contain 3-7 carbon atom with at least one selected from oxygen, sulfur With the heteroatomic monounsaturated or polyunsaturated monocycle of nitrogen, and its benzo-fused analog can be included.Suitably C3-7Heterocycloalkenyl includes thiazolinyl, imidazolinyl, dihydro pyranyl, dihydro thiapyran base, 1,2,3,6-tetrahydro pyridyl and 1- H-pyridin-2-ones.
Term " C used herein4-9Miscellaneous bicyclic alkyl " correspond to wherein one or more carbon atoms by one Or the C that the multiple hetero atom selected from oxygen, sulfur and nitrogen is replaced4-9Bicyclic alkyl.Typical miscellaneous bicyclic alkyl includes 3-azabicyclo [3.1.0] hexyl, 2-oxa--5-azabicyclo [2.2.1] heptane base, 6-azabicyclo [3.2.0] heptane base, 3-azepine are double Ring [3.1.1] heptane base, 3-azabicyclo [4.1.0] heptane base, 2-oxabicyclo [2.2.2] octyl, quininuclidinyl, 2-oxygen Miscellaneous-5-azabicyclo-[2.2.2] octyl, 3-azabicyclo [3.2.1] octyl, 8-azabicyclo [3.2.1] octyl, 3-oxa--8-azabicyclo [3.2.1] octyl, 3,8-diazabicyclo [3.2.1] octyl, 3-azabicyclo [3.2.1] Octyl, 3,6-diazabicyclo [3.2.2] nonyl, 3-oxa--7-azabicyclo [3.3.1] nonyl, 3,9-diaza Dicyclo [4.2.1] nonyl and 3,7-dioxa-9-azabicyclo [3.3.1] nonyl.
Term " C used herein4-9Spiroheterocyclic alkyl " represent containing 4-9 carbon atom and at least one be selected from oxygen, Sulfur and the heteroatomic saturated bicyclic ring system of nitrogen, wherein said two rings are connected by a common member.Suitably spiroheterocyclic Alkyl includes 5-azaspiro [2.3] hexyl, 5-azaspiro-[2.4] heptane base, 2-azepine spiroheptane base, 2-oxa-- 6-azepine spiroheptane base, 2-oxa--6-azaspiro-[3.4] octyl, 2-oxa--6-azaspiro [3.5] nonyl, 7- Oxa--2-azaspiro [3.5] nonyl, 2-oxa--7-azaspiro [3.5] nonyl and 2,4,8-thriazaspiro [4.5] decane Base.
Term " heteroaryl " expression used herein contains at least 5 from what a monocycle or multiple fused rings derived The monovalent aromatic group of individual atom, wherein one or more carbon atoms are by one or more miscellaneous former selected from oxygen, sulfur and nitrogen Son is replaced.Suitably heteroaryl includes furyl, benzofuranyl, dibenzofuran group, thienyl, benzothienyl, thiophene And [2,3-c] pyrazolyl, thieno [3,4-b] [1,4] dioxine base (dioxinyl), dibenzothiophenes base, pyrroles Base, indyl, 2,3-dihydro-1H-isoindolyl, pyrrolo-[2,3-b] pyridine radicals, pyrrolo-[3,2-c] pyridine radicals, pyrrolo- [3,4-b] pyridine radicals, pyrazolyl, pyrazolo [1,5-a] pyridine radicals, pyrazolo [3,4-d] pyrimidine radicals, indazolyl, 4,5,6,7- Tetrahydrochysene indazole base,Oxazolyl, benzoOxazolyl, differentOxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazole radicals, benzene And imidazole radicals, imidazo [2,1-b] thiazolyl, imidazo [1,2-a] pyridine radicals, imidazo [4,5-b] pyridine radicals, purine radicals, Imidazo [1,2-a] pyrimidine radicals, imidazo [1,2-a] pyrazinyl,Di azoly, thiadiazolyl group, triazolyl, [1,2,4] triazole And [1,5-a] pyrimidine radicals, benzotriazole base, tetrazole radical, pyridine radicals, quinolyl, isoquinolyl, naphthyridinyl, pyridazinyl, cinnolines Base, phthalazinyl, pyrimidine radicals, quinazolyl, pyrazinyl, quinoxalinyl, pteridine radicals, triazine radical and chromenyl.
Term " amino " representative formula-NR used hereinbRcGroup, wherein RbAnd RcAs defined herein.
Term " halogen " used herein is intended to include fluorine, chlorine, bromine and atomic iodine, typically fluorine, chlorine or bromine.
When the compound of formula (I) has one or more asymmetric center, they can be correspondingly as enantiomerism Body exists.When the compound used in the present invention has two or more asymmetric center, they can be additionally as non- Enantiomer exists.The present invention should be understood to extend to use all such enantiomers and diastereomer, And the mixture existed in any proportion, including racemic modification.Unless otherwise indicated or outside confirming, formula (I) and hereinafter retouching The formula stated is intended to represent all single stereoisomers and all possible mixture thereof.It addition, the compound of formula (I) can be made Exist for tautomer, such asTautomer or Tautomer.Unless otherwise indicated or confirm outside, formula (I) and under Formula described in literary composition is intended to represent all single tautomers and all possible mixture thereof.
Should be appreciated that in formula (I) or present in formula described below each individual atom can in fact with Presented in any one in its naturally occurring isotope, the abundantest isotope is preferred.Thus, as example Son, in formula (I) or present in formula described below, each independent hydrogen atom can conduct1H、2H (deuterium) or3H (tritium) Atom exists, preferably1H.Similarly, by way of example, each independent carbon in formula (I) or present in formula described below Atom can conduct12C、13C or14C atom exists, preferably12C。
In the first embodiment, n represents the integer equal to 0.
In second embodiment, n represents the integer equal to 1.
In one embodiment, X represents covalent bond；Or hetero atom；Or-S (O) ,-S (O)2、-S(O)(N-Rd)、-NC (O)Rd、-N(CO)-ORd、-NS(O)2RdOr-N (Rd)；Or the straight or branched C being optionally substituted1-4Alkylidene chain；And
Z represents the straight or branched C being optionally substituted1-4Alkylidene chain.
In another embodiment, X represents the straight or branched C being optionally substituted1-4Alkylidene chain；And
Z represents covalent bond；Or hetero atom；Or-S (O) ,-S (O)2、-S(O)(N-Rd)、-NC(O)Rd、-N(CO)-ORd、- NS(O)2RdOr-N (Rd)；Or the straight or branched C being optionally substituted1-4Alkylidene chain.
Typically, X represents hetero atom-S (O) or-N-Rd；Or the straight or branched C being optionally substituted1-4Alkylidene chain；
In the first embodiment, X represents covalent bond.
In second embodiment, X represents hetero atom.At an aspect of this embodiment, X is oxygen.In this enforcement Second aspect X of scheme is sulfur.
In a third embodiment, X represents-S (O).
In the 4th embodiment, X represents-S (O)2。
In the 5th embodiment, X represents-S (O) (N-Rd)。
In the 6th embodiment, X represents-NC (O) Rd。
In the 7th embodiment, X represents-N (CO)-ORd。
In the 8th embodiment, X represents-NS (O)2Rd。
In the 9th embodiment, X represents-N (Rd).At a particular aspects of this embodiment, X representative-NH.
In the tenth embodiment, X represents the straight or branched C being optionally substituted1-4Alkylidene chain.Real according to this Executing scheme, the representative value of X includes methylene (-CH2-), (methyl) methylene, ethylidene (-CH2CH2-), (ethyl) methylene, (dimethyl)-methylene, (methyl) ethylidene, propylidene (-CH2CH2CH2-), (propyl group) methylene and (dimethyl) ethylidene, Any one in described chain can optionally be substituted with one or more substituents.At an aspect of this embodiment, X represents Unsubstituted straight or branched C1-4Alkylidene chain.In the second aspect of this embodiment, X represents mono-substituted straight chain or props up Chain C1-4Alkylidene chain.In the third aspect of this embodiment, X represents dibasic straight or branched C1-4Alkylidene chain.
In the 11st embodiment, X represents carbonyl.
The occurrence of X includes methylene ,-S (O), oxygen or sulfur.
Generally, Z represents covalent bond；Or hetero atom；Or-S (O) ,-S (O)2、-S(O)(N-Rd)、-NC(O)Rd、-N(CO)- ORd、-NS(O)2RdOr-N (Rd)；Or the straight or branched C being optionally substituted1-4Alkylidene chain.
Typically, Z represents covalent bond；Or hetero atom；Or-NC (O) Rd、-N(CO)-ORd、-NS(O)2RdOr-N (Rd)；Or The straight or branched C being optionally substituted1-4Alkylidene chain.
In the first embodiment, Z represents covalent bond.In second embodiment, Z represents hetero atom.Real at this Executing an aspect of scheme, Z is oxygen.It is sulfur in second aspect Z.In a third embodiment, Z represents-S (O).At the 4th In embodiment, Z represents-S (O)2.In the 5th embodiment, Z represents-S (O) (N-Rd).In the 6th embodiment, Z represents-NC (O) Rd.In the 7th embodiment, Z represents-N (CO)-ORd.In the 8th embodiment, Z representative-NS (O)2Rd.In the 9th embodiment, Z represents-N (Rd).At a particular aspects of this embodiment, Z representative-NH.
In the tenth embodiment, Z represents the straight or branched C being optionally substituted1-4Alkylidene chain.According to this enforcement The representative value of the Z of scheme includes methylene (-CH2-), (methyl) methylene, ethylidene (-CH2CH2-), (ethyl) methylene, (dimethyl)-methylene, (methyl) ethylidene, propylidene (-CH2CH2CH2-), (propyl group) methylene and (dimethyl) ethylidene, Any one in described chain can optionally be substituted with one or more substituents.At an aspect of this embodiment, Z represents Unsubstituted straight or branched C1-4Alkylidene chain.In the second aspect of this embodiment, Z represents mono-substituted straight chain or props up Chain C1-4Alkylidene chain.In the third aspect of this embodiment, Z represents dibasic straight or branched C1-4Alkylidene chain.
In the 11st embodiment, Z represents carbonyl.
May reside in the example according to the Typical substituents on the alkylidene chain in the compound of the present invention include halogen, Hydroxyl, oxo, C1-6Alkoxyl, aryl ,-C (O) Rd、-CO2Rd、-CONRbRc-S(O)(N-Rd)RaWith-SO2NRbRc。
The occurrence of Z includes covalent bond, oxygen, sulfur ,-NH ,-NCH3、-N-(SO2)-CH3、-N-(CO)-CH3With-N-(CO)- O-CH3。
In one particular embodiment, X represents the straight or branched C being optionally substituted1-4Alkylidene chain；And
Z represents covalent bond；Or hetero atom；Or-NC (O) Rd、-N(CO)-ORd、-NS(O)2RdOr-N (Rd)；Or optionally by Substituted straight or branched C1-4Alkylidene chain.
In another particular, Z represents covalent bond；Or the straight or branched C being optionally substituted1-4Alkylene Base chain；And
X represents hetero atom；-S (O) or-N-Rd。
Generally, Y represents C3-7Cycloalkyl, aryl or heteroaryl, any one in described group can optionally by one or Multiple substituent groups replace.
Typically, Y represents aryl or heteroaryl, and any one in described group can be optionally by one or more replacements Base replaces.
In the first embodiment, Y represents optionally substituted C3-7Cycloalkyl.At an aspect of this embodiment, Y represents unsubstituted C3-7Cycloalkyl.At another aspect of this embodiment, Y represents mono-substituted C3-7Cycloalkyl.At this Another aspect of embodiment, Y represents dibasic C3-7Cycloalkyl.
In second embodiment, Y represents optionally substituted aryl.At an aspect of this embodiment, Y represents Unsubstituted aryl.At another aspect of this embodiment, Y represents mono-substituted aryl.At another of this embodiment Individual aspect, Y represents dibasic aryl.
In a third embodiment, Y represents optionally substituted C3-7Heterocyclylalkyl.A side in this embodiment Face, Y represents unsubstituted C3-7Heterocyclylalkyl.At another aspect of this embodiment, Y represents mono-substituted C3-7Heterocycle alkane Base.At another aspect of this embodiment, Y represents dibasic C3-7Heterocyclylalkyl.
In the 4th embodiment, Y represents optionally substituted heteroaryl.In an aspect of this embodiment, Y generation The unsubstituted heteroaryl of table.At another aspect of this embodiment, Y represents mono-substituted heteroaryl.In this embodiment Another aspect, Y represents disubstituted heteroaryl.
Suitably, Y represents benzocyclobutane thiazolinyl, phenyl, thienyl, thiazolyl, pyridine radicals, pyrimidine radicals or pyrazolyl, institute State any one in group can optionally be substituted with one or more substituents.
Suitably, Y represents phenyl, thienyl or thiazolyl, any one in described group can optionally by one or Multiple substituent groups replace.
Suitably, Y represents phenyl, and it can optionally be substituted with one or more substituents.
The example that may reside in the optionally substituted base in part Y includes that one, two or three is independently selected from following Substituent group: halogen, cyano group, nitro, C1-6Alkyl, trifluoromethyl, hydroxyl, C1-6Alkoxyl, difluoro-methoxy, trifluoro methoxy Base, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, (C1-6) alkylsulfonyloxy, amino, C1-6Alkyl-ammonia Base, two (C1-6) alkyl amino, arylamino, C2-6Alkyl-carbonyl-amino, C1-6Alkyl sulfonyl-amino, formoxyl, C2-6Alkyl Carbonyl, C3-6Naphthene base carbonyl, C3-6Heterocycloalkylcarbonyl, carboxyl, C2-6Alkoxy carbonyl, amino carbonyl, C1-6Alkyl amino carbonyl Base, two (C1-6) alkyl-aminocarbonyl, amino-sulfonyl, C1-6Alkyl amino sulfonyl and two (C1-6) alkyl amino sulfonyl.
The example of the concrete substituent group in part Y includes fluorine, chlorine, bromine, cyano group, nitro, methyl, isopropyl, fluoroform Base, hydroxyl, methoxyl group, difluoro-methoxy, trifluoromethoxy, methyl mercapto, methylsulfinyl, methyl sulphonyl, sulfonyloxy methyl Epoxide, amino, methylamino, tert-butylamino, dimethylamino, phenyl amino, acetyl-amino, anethane-sulfonyl amino, Formoxyl, acetyl group, cyclopropyl carbonyl, azelidinyl carbonyl, pyrrolidinyl-carbonyl, piperidino carbonyl, piperazinyl carbonyl, Morpholinyl carbonyl, carboxyl, methoxycarbonyl, amino carbonyl, methylaminocarbonyl, Dimethylaminocarbonyl, amino-sulfonyl, first Base amino-sulfonyl and dimethylamino-sulfonyl.The other example of the concrete substituent group on Y includes butoxy carbonyl.
The suitable example of the concrete substituent group in part Y includes chlorine, fluorine, cyano group, methoxyl group, methyl sulphonyl, trifluoro Methoxyl group difluoro-methoxy and butoxy carbonyl.
The exemplary of the concrete substituent group in part Y includes chlorine, fluorine, cyano group, methoxyl group, methyl sulphonyl, trifluoro Methoxyl group and difluoro-methoxy.
The representative value of Y includes that benzocyclobutane thiazolinyl, phenyl, (methyl sulphonyl) phenyl (include 4-methyl sulphonyl-benzene Base), benzonitrile (including 2-benzonitrile, 3-benzonitrile and 4-benzonitrile), fluorophenyl (including 2-fluorophenyl, 3-fluorophenyl and 4-fluorophenyl), Chlorphenyl (including the chloro-phenyl of 2-, 3-chlorphenyl and 4-chlorphenyl), difluorophenyl (including 2,6-difluorophenyl), (chlorine) (fluorine) Phenyl (including 5-chloro-2-fluorophenyl and 2-chloro-5-fluorophenyl), Dichlorobenzene base (include 2,5-Dichlorobenzene base and 2,6-dichloro-benzenes Base), aminomethyl phenyl (including 4-aminomethyl phenyl), 3,5-dimethylphenyl (including 2,5-3,5-dimethylphenyl and 2,6-3,5-dimethylphenyl), (trifluoromethyl) phenyl [including 2-(trifluoromethyl) phenyl], (chlorine) (trifluoromethyl) phenyl [include the chloro-2-of 5-(trifluoromethyl) Phenyl], (methyl)-(trifluoromethyl) phenyl [including 2-methyl-5-(trifluoromethyl) phenyl], double (TRIFLUORO-METHYL) phenyl [bag Include double (trifluoromethyl) phenyl of 2,5-], methoxyphenyl (including 2-methoxyphenyl), (difluoro-methoxy) phenyl [include 2- (difluoro-methoxy) phenyl, 3-(difluoro-methoxy) phenyl and 4-(difluoro-methoxy) phenyl], (double-(difluoro-methoxy)) benzene Base [include 2,5-(double-(difluoro-methoxy))-phenyl, and include 2,6-(double-(difluoro-methoxy))-phenyl], (difluoromethoxy Base) (fluorine) phenyl [includes 2-(difluoro-methoxy)-5-fluorophenyl, 2-(difluoro-methoxy)-3-fluorophenyl, 2-(difluoromethoxy Base)-6-fluorophenyl and 5-(difluoro-methoxy)-2-fluorophenyl], (difluoro-methoxy) (difluoro) phenyl (include 2-difluoromethoxy Base-3,5-difluorophenyl), (chlorine) (difluoro-methoxy) phenyl [include 2-chloro-5-(difluoro-methoxy) phenyl, the chloro-2-of 5-(two Fluorine methoxyl group) phenyl, 5-chloro-3-(difluoro-methoxy) phenyl and 6-chloro-2-(difluoro-methoxy) phenyl], (cyano group) (difluoro first Epoxide) [include that 6-cyano group-2-(difluoro-methoxy)-phenyl (trifluoromethoxy) phenyl [includes 2-(trifluoromethoxy)-benzene Base], sulfonyloxy methyl phenyl, (chlorine) (trifluoromethoxy) phenyl, [including 3-chloro-6-trifluoromethoxy-phenyl], (amino) (chlorine) phenyl [including the 5-chloro-phenyl of amino-2-], methylthiophene base [including 3 methyl thiophene-2-base], methyl thiazolium oxazolyl [bag Include 2-methyl-1,3-thiazole-4-base and 4-methyl-1,3-thiazole-4-base], (chlorine) thiazolyl [include 4-chloro-1,3-thiazole Base], (chlorine) (methyl) thiazolyl [including 5-chloro-2-methyl-1,3-thiazole-4-yl], dimethylthiazole base [include 2,4-diformazan Base-1,3-thiazole-5-base], pyridine radicals [including pyridin-3-yl and pyridin-4-yl], (methyl) (trifluoromethyl) thiazolyl [bag Include 2-methyl-4-Trifluoromethyl-1,3-thiazolyl], (dimethoxy) pyrimidine radicals [including 4,6-dimethoxy-pyridin-5-base] (methoxyl group) pyrazinyl [includes 5-methoxypyrazine base].The other particular value of Y includes (difluoro-methoxy) (butoxy carbonyl Base) phenyl [including 2-difluoro-methoxy-6-butyl epoxide carbonyl-phenyl].
Y definite value really include phenyl, (methyl sulphonyl) phenyl, benzonitrile chlorphenyl, (chlorine) (fluorine) phenyl, Dichlorobenzene base, 3,5-dimethylphenyl, (trifluoromethyl) phenyl, (difluoro-methoxy) phenyl, (double-(difluoro-methoxy)) phenyl (difluoro-methoxy) (fluorine) phenyl, (difluoro-methoxy) (cyano group) phenyl, (difluoro-methoxy) (difluoro) phenyl, (chlorine) (difluoro-methoxy) phenyl, (chlorine) (trifluoromethoxy) phenyl, (chlorine) (methyl) thiazolyl, (chlorine) thiazolyl, (methyl) (trifluoromethyl) thiazolyl, (diformazan Epoxide) pyrimidine radicals, (methoxyl group) pyrazinyl and (butoxy carbonyl)-(difluoro-methoxy) phenyl.The set point value of Y include phenyl, (methyl sulphonyl) phenyl, benzonitrile chlorphenyl, (chlorine) (fluorine) phenyl, Dichlorobenzene base, 3,5-dimethylphenyl, (trifluoromethyl) phenyl, (difluoro-methoxy) phenyl, (double-(difluoro-methoxy)) phenyl (difluoro-methoxy) (fluorine) phenyl, (difluoro-methoxy) (cyano group) Phenyl, (difluoro-methoxy) (difluoro) phenyl, (chlorine) (difluoro-methoxy) phenyl, (chlorine) (trifluoromethoxy) phenyl, (chlorine) (first Base) thiazolyl, (chlorine) thiazolyl, (methyl) (trifluoromethyl) thiazolyl, (dimethoxy) pyrimidine radicals and (methoxyl group) pyrazinyl. Other set point value includes (butoxy carbonyl) (difluoro-methoxy) phenyl.
The appropriate value of Y includes (difluoro-methoxy) phenyl, (difluoro-methoxy) (fluorine) phenyl, (chlorine) (difluoro-methoxy) benzene Base (difluoro-methoxy) (cyano group) phenyl and (butoxy carbonyl) (difluoro-methoxy) phenyl.
The particular value of Y includes (difluoro-methoxy) phenyl, (difluoro-methoxy) (fluorine) phenyl, (chlorine) (difluoro-methoxy) benzene Base and (difluoro-methoxy) (cyano group) phenyl.
The occurrence of Y includes 2-difluoro-methoxy-phenyl, the chloro-phenyl of 2-difluoro-methoxy-5-, 2-difluoro-methoxy-6- Chloro-phenyl, 2-difluoro-methoxy-6-fluoro-phenyl and 2-difluoro-methoxy-6-cvano-phenyl.The other occurrence of Y includes 2-difluoro-methoxy-6-butyl epoxide carbonyl-phenyl.
In one particular embodiment, Y represents 2-(difluoro-methoxy) phenyl.
Suitably, R1And R2Represent hydrogen, halogen, cyano group, trifluoromethyl independently；-S(O)2(N-Rd) or-CO2Rd；Or C1-6 Alkyl, C2-6Alkynyl, aryl, C3-7Heterocyclylalkyl, C3-7Heterocycloalkenyl, heteroaryl, (C3-7) Heterocyclylalkyl (C1-6) alkyl-virtue Base-, heteroaryl-(C3-7) Heterocyclylalkyl-, (C3-7) cycloalkyl-heteroaryl-, (C3-7) cycloalkyl (C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl-heteroaryl-, (C3-7) Heterocyclylalkyl-heteroaryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-heteroaryl-, (C4-9) miscellaneous bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic Alkyl-heteroaryl-, any one in described group can optionally be substituted with one or more substituents.
Typically, R2Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or-ORa；Or optionally The C being substituted with one or more substituents1-6Alkyl.
Generally, R3Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy；Or-ORa、-SRa、- SORa、-SO2Ra；Or the C being optionally substituted with one or more substituents1-6Alkyl.
Typically, R3Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or-ORa；Or optionally The C being substituted with one or more substituents1-6Alkyl.
Generally, R4Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy；Or-ORa、-SRa、- SORa、-SO2Ra；Or the C being optionally substituted with one or more substituents1-6Alkyl.
Typically, R4Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or-ORa；Or optionally The C being substituted with one or more substituents1-6Alkyl.
Generally, R5aRepresent hydrogen, hydroxyl, halogen, cyano group, trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-(CO)NRcRd、- NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)、-S(O)2(N-Rd)、-ORa、-C(O)2RdOr-O (CO)- Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heteroaryl, any one in described group can be optionally by one Or multiple substituent group replaces.
Generally, R5bRepresent hydrogen, hydroxyl, halogen, cyano group, trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-(CO)NRcRd、- NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)、-S(O)2(N-Rd)、-ORa、-C(O)2RdOr-O (CO)- Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl, heteroaryl, any one in described group can be optionally by one Or multiple substituent group replaces.
Suitably, R5aRepresent hydrogen, hydroxyl, halogen, cyano group, trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-(CO) NRcRd、-NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)、-S(O)2(N-Rd)、-ORa、-C(O)2Rd Or-O (CO)-Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl, heteroaryl, any one in described group can be optional Be substituted with one or more substituents；And
R5bRepresent hydrogen, hydroxyl, halogen, cyano group or trifluoromethyl；Or C1-6Alkyl, any one in described group can be appointed Selection of land is substituted with one or more substituents.
Alternatively, R5aAnd R5bCarbonyl, thiocarbonyl or-C=N-OH is represented together with the carbon being connected with them.
Generally, R6Represent hydrogen, hydroxyl, halogen, cyano group or trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-(CO)NRcRd、- NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)、-S(O)2(N-Rd)、-ORa、-C(O)2RdOr-O (CO)- Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heteroaryl, any one in described group can be optionally by one Or multiple substituent group replaces.
May reside in R1、R2、R3、R4、R5a、R5bAnd R6On the example of optionally substituted base include one, two or three Substituent group independently selected from following: halogen, halo-(C1-6) alkyl, cyano group, cyano group (C1-6) alkyl, nitro, nitro (C1-6) Alkyl, C1-6Alkyl, (C3-7) cycloalkyl, difluoromethyl, trifluoromethyl, two fluoro ethyls, trifluoroethyl, C2-6Thiazolinyl, hydroxyl, hydroxyl Base (C1-6) alkyl, C1-6Alkoxyl, difluoro-methoxy, trifluoromethoxy, trifluoro ethoxy, carboxyl (C3-7) cycloalkyl-epoxide, C1-3Alkylenedioxy group, C1-6Alkoxyl (C1-6) alkyl, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, oxo, amino, amino (C1-6) alkyl, C1-6Alkyl-amino, two (C1-6) alkyl ammonia Base, hydroxyl (C1-6) alkyl amino, C1-6Alkoxy amino, (C1-6) alkoxyl-(C1-6) alkyl amino, [(C1-6) alkoxyl] (hydroxyl Base) (C1-6) alkyl amino, [(C1-6) alkylthio group] (hydroxyl)-(C1-6) alkyl amino, N-[(C1-6) alkyl]-N-[hydroxyl (C1-6) Alkyl] amino, two (C1-6) alkyl amino-(C1-6) alkyl amino, N-[two (C1-6) alkyl amino (C1-6) alkyl]-N-[hydroxyl (C1-6) alkyl] amino, hydroxyl (C1-6) alkyl (C3-7) cycloalkyl amino, (hydroxyl) [(C3-7) cycloalkyl (C1-6) alkyl] amino, (C3-7) Heterocyclylalkyl (C1-6) alkyl amino, oxo (C3-7) Heterocyclylalkyl (C1-6) alkyl amino, (C1-6) miscellaneous alkyl aryl ammonia Base, heteroaryl (C1-6) alkyl amino, (C1-6) miscellaneous alkyl aryl (C1-6) alkyl-amino, C2-6Alkyl-carbonyl-amino, N-[(C1-6) Alkyl]-N-[(C2-6) alkyl-carbonyl] amino, (C2-6) alkyl-carbonylamino (C1-6) alkyl, C3-6Alkenylcarbonylamino, double [(C3-6) alkenyl carbonyl] amino, N-[(C1-6) alkyl]-N-[(C3-7) naphthene base carbonyl] amino, C2-6Alkoxycarbonyl amino, C2-6Alkoxy carbonyl (C1-6) alkyl amino, C1-6Alkyl amino-carbonyl-amino, C1-6Alkylsulfonyl-amino, N-[(C1-6) alkane Base]-N-[(C1-6) alkyl sulphonyl] amino, double [(C1-6) alkyl sulphonyl] amino, N-[(C1-6) alkyl]-N-[carboxyl (C1-6) alkyl] amino, carboxyl (C3-7) cycloalkyl amino, carboxyl-(C3-7) cycloalkyl (C1-6) alkyl amino, formoxyl, C2-6Alkane Base carbonyl, (C3-7) naphthene base carbonyl, phenylcarbonyl group, (C2-6) alkyl-carbonyl epoxide (C1-6) alkyl, carboxyl, carboxyl (C1-6) alkane Base, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, morpholinyl (C1-6) alkoxy carbonyl, C2-6Alkoxy carbonyl is sub- Methyl (methylidenyl), carboxylic acid isostere or prodrug moiety Ω ,-(C1-6) alkyl-Ω, amino carbonyl, C1-6Alkyl Amino carbonyl, hydroxyl (C1-6) alkylamino-carbonyl, two (C1-6) alkyl amino-carbonyl, amino carbonyl (C1-6) alkyl, amino sulphur Acyl group, two (C1-6) alkyl amino sulfonyl, (C1-6) alkyl sulfide sulfoximide base (sulphoximinyl), [(C1-6) alkyl] [N- (C1-6) alkyl]-sulfur sulfoximide base and heteroaryl.At R1、R2、R3、R4、R5a、R5bAnd R6On other example of optionally substituted base Including (C3-7) cycloalkyl-sulfonyl and hydroxyl (C1-6) alkyl amino sulfonyl.
Statement " carboxylic acid isostere or prodrug moiety " refers to be structurally different from any functional group of carboxylic moiety, Described functional group will be identified as being similar to carboxylic moiety by biosystem and be thus able to imitate carboxylic moiety, or can in vivo by Biosystem is readily converted into carboxylic moiety.N.A.Meanwell (sees at J.Med.Chem., 2011,54,2529-2591 Especially Figure 25 and 26) in present the summary about some common carboxylic acid isosteres.N Pemberton et al. is at ACS Med.Chem.Lett., 2012,3,574-578 describes a kind of substituting carboxylic acid isostere.The conjunction represented by Ω The exemplary of suitable carboxylic acid isostere or prodrug moiety includes that formula (i) is to the functional group of (xliii):
Wherein
Asterisk (*) represents the junction point of the remainder with described molecule；
N is 0,1 or 2；
Q represents oxygen or sulfur；
RfRepresent hydrogen, C1-6Alkyl or-CH2CH(OH)CH2OH；
RgRepresent C1-6Alkyl, trifluoromethyl ,-CH2CH2F、-CH2CHF2、-CH2CF3Or-CF2CF3；
RhRepresent hydrogen, cyano group or-CO2Rd, wherein RdAs defined above；And
RjRepresent hydrogen or halogen.
In one embodiment, n is 0.In another embodiment, n is 1.In another embodiment, n is 2。
In one embodiment, Q represents oxygen.In another embodiment, Q represents sulfur.
In one embodiment, RfRepresent hydrogen.In another embodiment, RfRepresent C1-6Alkyl, particularly methyl. In another embodiment, RfIt is-CH2CH(OH)CH2OH。
In one embodiment, RgRepresent C1-6Alkyl, particularly methyl.In another embodiment, RgRepresent three Methyl fluoride ,-CH2CH2F、-CH2CHF2、-CH2CF3Or-CF2CF3.At the first aspect of this embodiment, RgRepresent trifluoromethyl. At the second aspect of this embodiment, RgRepresentative-CH2CH2F.At the third aspect of this embodiment, RgRepresentative-CH2CHF2.? The fourth aspect of this embodiment, RgRepresentative-CH2CF3.At the 5th aspect of this embodiment, RgRepresentative-CF2CF3。
In one embodiment, RhIt is hydrogen.In another embodiment, RhRepresent cyano group.In another embodiment In, RhRepresentative-CO2Rd, particularly methoxycarbonyl.
In one embodiment, RjRepresent hydrogen.In another embodiment, RjRepresent halogen, particularly chlorine.
In a selected embodiment, Ω represents tetrazole radical, formula (xxiv) particularly as above or (xxv's) The tetrazolyl moiety that C-connects, the group of formula (xxiv) especially as above.
In another embodiment, Ω represents C1-6Alkylsulfonyl aminocarbonyl, formula (iii) i.e. as above Part, wherein RgRepresent C1-6Alkyl.
In another embodiment, Ω represents C1-6Alkyl amino sulfonyl, the part of formula (x) i.e. as above, its Middle RgRepresent C1-6Alkyl.
In another embodiment, Ω represents (C1-6) alkyl-carbonyl-amino sulfonyl, formula (v) i.e. as above Part, wherein RgRepresent C1-6Alkyl.
At R1、R2、R3、R4、R5a、R5bAnd R6On the example of concrete substituent group include fluorine, chlorine, bromine, methyl fluoride, fluorine isopropyl Base, cyano group, cyano ethyl, nitro, nitromethyla, methyl, ethyl, isopropyl, isobutyl group, the tert-butyl group, cyclopropyl, difluoro first Base, trifluoromethyl, two fluoro ethyls, trifluoro ethyl, vinyl, hydroxyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, isopropyl oxygen Base, difluoro-methoxy, trifluoromethoxy, trifluoro ethoxy, carboxyl cyclobutoxy group, methylene-two epoxide, ethylene epoxide, Methoxy, methoxy ethyl, methyl mercapto, methylsulfinyl, methyl sulphonyl, methysulfonylethyl, oxo, ammonia Base, amino methyl, amino isopropyl, methylamino, ethylamino, dimethylamino, hydroxyethylamino, hydroxypropyl, (hydroxyl Base) (methyl) propylcarbamic, Methoxyamino, methoxyethylamino, (hydroxyl)-(methoxyl group) (methyl) propylcarbamic, (hydroxyl Base) (methyl mercapto) butylamino, N-(ethoxy)-N-(methyl) amino, Dimethylaminoethylamino, (dimethylamino) (methyl) propylcarbamic, N-(dimethyl aminoethyl)-N-(ethoxy) amino, hydroxymethyl clopentylamino, hydroxyl ring fourth Vlmethyl, (cyclopropyl) (hydroxyl) propylcarbamic, morpholinyl ethyl-amino, oxo-pyrrolidine vlmethyl, ethylDi azoly amino, methyl thiazolium di azoly amino, benzothiazolylmethyl amino, thiazolylethyl amino, Pyrimidylmethyl amino, Methylpyrazole base-methylamino, acetyl-amino, N-acetyl group-N-methylamino, N-Isopropylcarbonyl-N-Methyl-amino, Acetylaminomethyl, ethenylcarbonylamino, double (vinyl carbonyl) amino, N-cyclopropyl carbonyl-N-methylamino, methoxy Base carbonylamino, ethoxycarbonylamino group, tertbutyloxycarbonylamino, dion e amino, ethyl aminocarbonyl ammonia Base, butylamino carbonylamino, Methylsulfonylamino, N-methyl-N-(methyl sulphonyl) amino, double (methyl sulphonyl) ammonia Base, N-(carboxymethyl)-N-methylamino, N-(carboxy ethyl)-N-methylamino, carboxyl clopentylamino, carboxycyclopropyl first Base amino, formoxyl, acetyl group, Isopropylcarbonyl, cyclobutyl carbonyl, phenylcarbonyl group, acetoxyl group isopropyl, carboxyl, carboxylic first Base, carboxy ethyl, methoxycarbonyl, ethoxy carbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, Methoxycarbonylmethyl, second Epoxide carbonvlmethyl, ethoxycarbonylethyl group, morpholinyl ethoxy carbonyl, ethoxycarbonylmethylene, Methylsulfonylamino- Carbonyl, acetyl-amino sulfonyl, Methoxyamino carbonyl, tetrazole radical, tetrazole radical methyl, hydroxylDi azoly, amino carbonyl Base, methylaminocarbonyl, hydroxyethyl aminocarbonyl, Dimethylaminocarbonyl, amino carbonyl methyl, amino-sulfonyl, methyl ammonia Base sulfonyl, dimethylamino-sulfonyl, methyl sulfur sulfoximide base, (methyl) (N-methyl) sulfur sulfoximide base and triazolyl.? R1、R2、R3、R4、R5a、R5bAnd R6On the other example of concrete substituent group include cyanoisopropyl, cyclopropyl-sulfonyl, isopropyl Base sulfonyl and (hydroxyl) ethylaminosulfonyl.
At R1、R2、R3、R4、R5a、R5bAnd R6On the suitable example of concrete substituent group include fluorine, hydroxyl, methyl-sulphonyl Base, methyl, isopropyl, methoxyl group, ethoxy carbonyl, cyclopropyl, cyclobutyl, carboxyl, methyl sulfur sulfoximide base, acetyl group, cyanogen Base isopropyl, cyclopropyl-sulfonyl, isopropelsulfonyl and (hydroxyl) ethylaminosulfonyl.
At R1、R2、R3、R4、R5a、R5bAnd R6On the exemplary of concrete substituent group include fluorine, hydroxyl, methyl-sulphonyl Base, methyl, isopropyl, methoxyl group, ethoxy carbonyl, cyclopropyl, cyclobutyl, carboxyl, methyl sulfur sulfoximide base and acetyl group.
Typically, R1Represent hydrogen, halogen, cyano group or-CO2Rd；Or C1-6Alkyl, C2-6Alkynyl, aryl, C3-7Heterocyclylalkyl, C3-7Heterocycloalkenyl, heteroaryl, (C3-7) Heterocyclylalkyl (C1-6) alkyl-aryl-group-, heteroaryl (C3-7) Heterocyclylalkyl-, (C3-7) ring Alkyl-heteroaryl-, (C3-7) cycloalkyl (C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl- Heteroaryl-, (C3-7) Heterocyclylalkyl-heteroaryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-miscellaneous Aryl-, (C4-9) miscellaneous bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl-, any one in described group is permissible Optionally it is substituted with one or more substituents.
Suitably, R1Represent halogen, cyano group or-CO2Rd；Or C1-6Alkyl, C2-6Alkynyl, aryl, C3-7Heterocyclylalkyl, C3-7 Heterocycloalkenyl, heteroaryl, (C3-7) Heterocyclylalkyl-(C1-6) alkyl-aryl-group-, heteroaryl (C3-7) Heterocyclylalkyl-, (C3-7) cycloalkanes Base-heteroaryl-, (C3-7) cycloalkyl (C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl-miscellaneous Aryl-, (C3-7) Heterocyclylalkyl-heteroaryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-heteroaryl Base-, (C4-9) miscellaneous bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl-, any one in described group can be appointed Selection of land is substituted with one or more substituents.
Generally, R1Represent halogen or cyano group；Or C1-6Alkyl, C2-6Alkynyl, aryl, C3-7Heterocyclylalkyl, C3-7Heterocycloalkenyl, Heteroaryl, (C3-7) Heterocyclylalkyl (C1-6) alkyl-aryl-group-, heteroaryl (C3-7) Heterocyclylalkyl-, (C3-7) cycloalkyl-heteroaryl-, (C3-7) cycloalkyl-(C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl-heteroaryl-, (C3-7) Heterocyclylalkyl-heteroaryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-heteroaryl-, (C4-9) miscellaneous Bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl-, any one in described group can be optionally by one Or multiple substituent group replaces.
Suitably, R1Represent aryl, (C3-7) heterocycloalkenyl-, heteroaryl, (C3-7) Heterocyclylalkyl-heteroaryl-, (C4-9) miscellaneous Bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl, any one in described group can optionally by one or Multiple substituent groups replace.
More generally, R1Represent aryl, heteroaryl or (C3-7) Heterocyclylalkyl-heteroaryl-, arbitrary in described group Individual can optionally be substituted with one or more substituents.
In the first embodiment, R1Represent hydrogen.
In second embodiment, R1Represent halogen.At an aspect of this embodiment, R1Represent bromine.
In a third embodiment, R1Represent cyano group.
In the 4th embodiment, R1Representative-CO2Rd。
In the 5th embodiment, R1Represent optionally substituted C1-6Alkyl.At an aspect of this embodiment, R1 Represent optionally substituted ethyl.
In the 6th embodiment, R1Represent optionally substituted C2-6Alkynyl.At an aspect of this embodiment, R1 Represent optionally substituted butynyl.
In the 7th embodiment, R1Represent optionally substituted aryl.At an aspect of this embodiment, R1Generation The optionally substituted phenyl of table.
In the 8th embodiment, R1Represent optionally substituted C3-7Heterocyclylalkyl.
In the 9th embodiment, R1Represent optionally substituted C3-7Heterocycloalkenyl.A side in this embodiment Face, R1Represent optionally substituted 1H-pyridin-2-ones.
In the tenth embodiment, R1Represent optionally substituted heteroaryl.At the selected aspect of this embodiment, R1 Represent benzofuranyl, thienyl, indyl, pyrazolyl, indazolyl, differentOxazolyl, thiazolyl, imidazole radicals, pyridine radicals, quinoline Quinoline base, pyridazinyl, pyrimidine radicals or pyrazinyl, any one in described group can optionally be taken by one or more substituent groups Generation.
In the 11st embodiment, R1Represent optionally substituted (C3-7)-Heterocyclylalkyl (C1-6) alkyl-aryl-group-. At the first aspect of this embodiment, R1Represent optionally substituted pyrrolidinylmethyl phenyl-.In this embodiment second Aspect, R1Represent optionally substituted piperizinylmethyl phenyl-.
In the 12nd embodiment, R1Represent optionally substituted heteroaryl (C3-7)-Heterocyclylalkyl-.In this enforcement One aspect of scheme, R1Represent optionally substituted Pyridylpiperazine base-.
In the 13rd embodiment, R1Represent optionally substituted (C3-7) cycloalkyl-heteroaryl-.This embodiment party The first aspect of case, R1Represent optionally substituted cyclohexyl pyrazolyl-.At the second aspect of this embodiment, R1Represent optionally The substituted cyclohexylmethylpyridine base in ground-.At the third aspect of this embodiment, R1Represent optionally substituted cyclopropyl-pyrimidine base-. At the fourth aspect of this embodiment, R1Represent optionally substituted cyclobutyl pyrimidines base-.The 5th side in this embodiment Face, R1Represent optionally substituted cyclopenta pyrimidine radicals-.At the 6th aspect of this embodiment, R1Represent optionally substituted ring Hexyl pyrimidine radicals-.At the 7th aspect of this embodiment, R1Represent optionally substituted cyclohexyl-pyrazinyl-.In this enforcement The eighth aspect of scheme, R1Represent optionally substituted cyclopropyl pyridine base.
In the 14th embodiment, R1Represent optionally substituted (C4-7)-cycloalkenyl group-heteroaryl-.
In the 15th embodiment, R1Represent optionally substituted (C3-7)-Heterocyclylalkyl-heteroaryl-.Real at this Execute the first aspect of scheme, R1Represent optionally substituted pyrollidinopyridine base-.At the second aspect of this embodiment, R1Generation Table optionally substituted THP trtrahydropyranyl pyridine radicals-.At the third aspect of this embodiment, R1Represent optionally substituted piperidines Yl pyridines base-.At the fourth aspect of this embodiment, R1Represent optionally substituted piperazinyl pyridine base-.In this embodiment The 5th aspect, R1Represent optionally substituted morpholinyl pyridine radicals-.At the 6th aspect of this embodiment, R1Represent optionally Substituted thio-morpholinyl-pyridine radicals-.At the 7th aspect of this embodiment, R1Represent optionally substituted diaza cycloheptyl Yl pyridines base-.At the eighth aspect of this embodiment, R1Represent optionally substituted oxetanylmethoxy pyrimidine radicals-.In this enforcement 9th aspect of scheme, R1Represent optionally substituted azelidinyl pyrimidine radicals-.At the tenth aspect of this embodiment, R1Generation Table optionally substituted tetrahydrofuran base pyrimidine radicals-.At the 11st aspect of this embodiment, R1Represent optionally substituted pyrrole Cough up alkyl base-.At the 12nd aspect of this embodiment, R1Represent optionally substituted THP trtrahydropyranyl-pyrimidine radicals-. At the 13rd aspect of this embodiment, R1Represent optionally substituted piperidinyl pyrimidine base-.In this embodiment the 14th Aspect, R1Represent optionally substituted piperazinylpyrimidine base-.At the 15th aspect of this embodiment, R1Represent and optionally replace Morpholinyl pyrimidine radicals-.At the 16th aspect of this embodiment, R1Represent optionally substituted thio-morpholinyl-pyrimidine Base-.At the 17th aspect of this embodiment, R1Represent optionally substituted azacycloheptyl pyrimidine radicals-.In this embodiment The 18th aspect, R1Represent optionally substituted oxaza heptyl-pyrimidine base-.At the 19th aspect of this embodiment, R1 Represent optionally substituted diazacyclo heptyl-pyrimidine base-.At the 20th aspect of this embodiment, R1Represent and optionally replace Thia diazacyclo heptyl-pyrimidine radicals-.At the 21st aspect of this embodiment, R1Represent optionally substituted oxa- Cyclobutyl pyrazinyl-.At the 22nd aspect of this embodiment, R1Represent optionally substituted piperidyl pyrazinyl-.At this 23rd aspect of embodiment, R1Represent optionally substituted THP trtrahydropyranyl pyridine radicals.In this embodiment second 13 aspects, R1Represent (imino group) (oxo) thiazine alkyl-pyrimidinyl group.At the twenty-fourth aspect of this embodiment, R1Represent (oxo) thiazine alkyl-pyrimidinyl group.At the 25th aspect of this embodiment, R1Represent and (dioxo) thiazine alkyl-phonetic Piperidinyl.
In the 16th embodiment, R1Represent optionally substituted (C3-7)-Heterocyclylalkyl (C1-6) alkyl-heteroaryl Base-.At the first aspect of this embodiment, R1Represent optionally substituted morpholinyl methyl thienyl-.In this embodiment Second aspect, R1Represent optionally substituted morpholinyl ethyl pyrazolyl-.
In the 17th embodiment, R1Represent optionally substituted (C3-7)-heterocycloalkenyl-heteroaryl-.
In the 18th embodiment, R1Represent optionally substituted (C4-9)-miscellaneous bicyclic alkyl-heteroaryl-.At this One aspect of embodiment, R1Represent optionally substituted 3,7-dioxa-9-azabicyclo [3.3.1] nonyl-pyrimidine Base.At another aspect of this embodiment, R1Represent optionally substituted 3-azabicyclo [3.2.1] octyl-pyrimidine radicals.
In nineteen embodiment, R1Represent optionally substituted (C4-9)-spiroheterocyclic alkyl-heteroaryl-.At this One aspect of embodiment, R1Represent optionally substituted 2-oxa--7-aza-spiro [3,5] nonyl-pyrimidine radicals.
In the 20th embodiment, R1Represent optionally substituted (C3-7) cycloalkyl-(C1-6) alkyl-heteroaryl-. At an aspect of this embodiment, R1Represent optionally substituted cyclohexyl methyl pyrimidine radicals-.
In the 21st embodiment, R1Represent optionally substituted (C4-9)-bicyclic alkyl-heteroaryl-.
Suitably, R1Represent hydrogen, bromine, cyano group or-CO2Rd；Or ethyl, butynyl, phenyl, pyrrolidinyl, piperidyl, piperazine Piperazine base, morpholinyl, 1,2,3,6-tetrahydro pyridyl, benzofuranyl, thienyl, indyl, pyrazolyl, indazolyl, differentAzoles Base, thiazolyl, imidazole radicals, pyridine radicals, quinolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrrolidinylmethyl phenyl, piperazinyl first Base phenyl, Pyridylpiperazine base, cyclohexyl pyrazolyl, cyclohexylmethylpyridine base, cyclopropyl-pyrimidine base, cyclobutyl pyrimidines base, ring penta Yl pyrimidines base, cyclohexyl-pyrimidine radicals, cyclohexyl pyrazinyl, cyclohexyl methyl pyrimidine radicals, cyclohexenyl group pyridine radicals, cyclopropyl pyrrole Piperidinyl, cyclohexenyl group pyrimidine radicals, bicyclo-[3.1.0] hexyl pyridine radicals, bicyclo-[3.1.0] hexyl-pyrimidine radicals, bicyclo- [4.1.0] heptane yl pyrimidines base, bicyclo-[2.2.2] octyl pyrimidine radicals, pyrollidinopyridine base, THP trtrahydropyranyl pyridine radicals, Piperidinopyridine base, piperazinyl-pyridine base, morpholinyl pyridine radicals, thio-morpholinyl pyridine radicals, Diazesuberane yl pyridines Base, oxetanylmethoxy pyrimidine radicals, azelidinyl pyrimidine radicals, tetrahydrofuran base pyrimidine radicals, pyrrolidinyl-pyrimidine radicals, tetrahydrochysene pyrrole Mutter yl pyrimidines base, piperidinyl pyrimidine base, piperazinyl-pyrimidine radicals, hexahydro-[1,2,5] thiadiazoles also [2,3-a] pyrazinyl pyrimidine Base, morpholinyl-pyrimidine radicals, thio-morpholinyl pyrimidine radicals, azepan yl pyrimidines base, oxaza heptane yl pyrimidines base, two Azepan yl pyrimidines base, thia Diazesuberane yl pyrimidines base, oxetanylmethoxy pyrazinyl, piperidyl-pyrazinyl, Quinoline ylmethylthiophen base, morpholinyl ethyl pyrazolyl, 3-azabicyclo [3.1.0]-hexyl pyridine radicals, 3-azabicyclo [3.1.0] hexyl pyridazinyl, 3-azabicyclo [3.1.0] hexyl-pyrimidine radicals, 2-oxa--5-azabicyclo [2.2.1] heptan Alkyl base, 3-azabicyclo [3.1.1] alkyl-pyrimidinyl group in heptan, 3-azabicyclo [4.1.0] Alkylpyridyl in heptan, 3-nitrogen Miscellaneous dicyclo [4.1.0] alkyl-pyrimidinyl group in heptan, 2-oxabicyclo [2.2.2] octyl pyrimidine radicals, 3-azabicyclo [3.2.1] are pungent Alkyl-pyrimidinyl group, 8-azabicyclo [3.2.1] octyl pyrimidine radicals, 3-oxa--8-azabicyclo [3.2.1] octyl-pyrimidine Base, 3,6-diazabicyclo [3.2.2] nonyl pyrimidine radicals, 3-oxa--7-azabicyclo [3.3.1]-nonyl pyrimidine radicals, 5- Azaspiro [2.3] hexyl pyrimidine radicals, 5-azaspiro [2.4] alkyl-pyrimidinyl group in heptan, 2-azepine spiroheptane yl pyrimidines base, 2-oxa--6-azepine spiroheptane base-pyrimidine radicals, 2-oxa--6-azaspiro [3.4] octyl pyrimidine radicals, 2-oxa--6- Azaspiro [3.5] nonyl-pyrimidine radicals, 2-oxa--7-azaspiro [3.5] nonyl pyrimidine radicals, 2,4,8-thriazaspiro [4.5] Decyl-pyrimidine radicals, (imino group) (oxo) thiazine alkyl-pyrimidinyl group, (oxo) thiazine alkyl-pyrimidinyl group or (dioxo) thiophene Piperazine alkyl-pyrimidinyl group, any one in described group can optionally be substituted with one or more substituents.It addition, R1Represent The 1H-pyridin-2-ones being optionally substituted with one or more substituents.
Suitably, R1Represent phenyl, THP trtrahydropyranyl pyrimidine radicals, oxetanylmethoxy pyrimidine radicals, THP trtrahydropyranyl pyridine radicals, Pyrimidine radicals, pyrazolyl, pyridine radicals, pyrimidine radicals, morpholinyl pyrimidine radicals, piperazinyl pyridine base, Diazesuberane yl pyrimidines base, 3- Azabicyclo [3.2.1] octyl pyrimidine radicals, piperidinyl pyrimidine base, cyclobutyl pyrimidines base, (imino group) (oxo) thiazine alkyl- Pyrimidine radicals, (oxo) thiazine alkyl-pyrimidinyl group, (dioxo) thiazine alkyl-pyrimidinyl group, 2-oxa--7-azaspiro [3.5] nonane Base-pyrimidine radicals, 3,7-dioxa-9-azabicyclo [3.3.1] nonyl-pyrimidine radicals, 3-azabicyclo [3.2.1] octyl- Pyrimidine radicals or 1H-pyridin-2-ones, any one in described group can optionally be substituted with one or more substituents.
Exemplarily, R1Represent phenyl, THP trtrahydropyranyl pyrimidine radicals, oxetanylmethoxy pyrimidine radicals, Pentamethylene oxide. yl pyridines Base, pyrimidine radicals, pyrazolyl, pyridine radicals, pyrimidine radicals, morpholinyl pyrimidine radicals, piperazinyl pyridine base, Diazesuberane yl pyrimidines Base, 3-azabicyclo [3.2.1] octyl pyrimidine radicals, piperidinyl pyrimidine base, cyclobutyl pyrimidines base, (imino group) (oxo) thiazine Alkyl-pyrimidinyl group, (oxo) thiazine alkyl-pyrimidinyl group or (dioxo) thiazine alkyl-pyrimidinyl group, any one in described group Can optionally be substituted with one or more substituents.
At R1On the exemplary of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, halo (C1-6) alkyl, cyano group, cyano group (C1-6) alkyl, nitro (C1-6) alkyl, C1-6Alkyl, (C3-7) cycloalkyl, three Methyl fluoride, trifluoroethyl, C2-6Thiazolinyl, hydroxyl, hydroxyl (C1-6) alkyl, C1-6Alkoxyl, trifluoro ethoxy, carboxyl (C3-7) cycloalkanes Epoxide, C1-6Alkylthio group, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, oxo, amino, amino-(C1-6) alkane Base, C1-6Alkyl amino, two (C1-6) alkyl amino, (C1-6) alkoxyl (C1-6) alkyl amino, N-[(C1-6) alkyl]-N-[hydroxyl (C1-6) alkyl] amino, (C2-6) alkyl-carbonyl-amino (C1-6) alkyl, C1-6Alkyl sulfonyl-amino, N-[(C1-6) alkyl]-N- [(C1-6) alkyl sulphonyl] amino, double [(C1-6) alkyl-sulfonyl base] amino, N-[(C1-6) alkyl]-N-[carboxyl (C1-6) alkane Base] amino, carboxyl (C3-7) cycloalkyl-amino, carboxyl (C3-7) cycloalkyl (C1-6) alkyl amino, formoxyl, C2-6Alkyl-carbonyl, (C2-6) alkyl-carbonyloxy base (C1-6) alkyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, morpholinyl (C1-6) alkoxy carbonyl, C2-6Alkoxy carbonyl-methylene, amino carbonyl, amino-sulfonyl, (C1-6) alkyl sulfide sulfoximide base and [(C1-6) alkyl] [N-(C1-6) alkyl] sulfur sulfoximide base.At R1On optionally substituted base Other example includes (C3-7) cycloalkyl-sulfonyl and hydroxyl (C1-6) alkyl amino sulfonyl.
At R1On the suitable example of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, C-6Alkyl-carbonyl, (hydroxyl) C1-6Alkyl, (C3-7) cycloalkyl, C1-6Alkyl sulphur Acyl group, (C1-6) alkyl sulphonyl (C1-6) alkyl, (C1-6) alkyl sulfide sulfoximide base, heteroaryl, oxo, carboxyl, (cyano group) C1-6 Alkyl, (halo) C1-6Alkyl, amino-sulfonyl, (C3-7) cycloalkyl-sulfonyl and hydroxyl (C1-6) alkyl amino sulfonyl.
At R1On the suitable example of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, C-6Alkyl-carbonyl, (hydroxyl) C1-6Alkyl, (C3-7) cycloalkyl, C1-6Alkyl sulphur Acyl group, (C1-6) alkyl sulphonyl (C1-6) alkyl, (C1-6) alkyl sulfide sulfoximide base, heteroaryl, oxo and carboxyl.
At R1On the exemplary of concrete substituent group include that one, two or three is independently selected from following replacement Base: fluorine, chlorine, methyl fluoride, fluorine isopropyl, cyano group, cyano ethyl, nitromethyla, methyl, ethyl, isopropyl, isopropyl methyl, Cyclopropyl, cyclobutyl, trifluoromethyl, trifluoroethyl, vinyl, hydroxyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, isopropyl oxygen Base, trifluoro-ethoxy, carboxyl cyclobutoxy group, methyl mercapto, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl, Oxo, amino, amino methyl, amino isopropyl, methylamino, dimethylamino, methoxyethylamino, N-(ethoxy)- N-(methyl) amino, acetylaminomethyl, Methylsulfonylamino, N-methyl-N-(methyl sulphonyl) amino, double (methyl Sulfonyl) amino, N-(carboxy ethyl)-N-(methyl) amino, carboxyl clopentylamino, carboxycyclopropyl methylamino, formyl Base, acetyl group, acetoxyl group isopropyl, carboxyl, carboxymethyl, carboxy ethyl, methoxycarbonyl, ethoxy carbonyl, n-butoxy Carbonyl, tert-butoxycarbonyl, Methoxycarbonylmethyl, ethoxy-carbonyl methyl, ethoxycarbonylethyl group, morpholinyl ethyoxyl Carbonyl, ethoxycarbonyl-methylene, Methylsulfonylamino carbonyl, acetyl-amino sulfonyl, Methoxyamino-carbonyl, four Oxazolyl, tetrazole radical methyl, hydroxylDi azoly, amino carbonyl, amino-sulfonyl, methyl sulfur sulfoximide base and (methyl) (N- Methyl) sulfur sulfoximide base.At R1On other example of concrete substituent group include cyanoisopropyl, cyclopropyl-sulfonyl, isopropyl Base sulfonyl and (hydroxyl) ethylaminosulfonyl
At R1On the object lesson of substituent group include that one, two or three is independently selected from following substituent group: fluorine, Methyl, isopropyl, isopropyl methyl, sulfonyloxy methyl ylmethyl, hydroxyisopropyl, cyclopropyl, cyclobutyl, methyl sulphonyl, carboxylic Base, hydroxymethyl, acetyl group, methyl sulfur sulfoximide base, oxo, Methoxyamino-sulfonyl, cyanoisopropyl, cyclopropyl-sulphur Acyl group, isopropelsulfonyl and (hydroxyl) ethylaminosulfonyl.
In one particular embodiment, R1By hydroxyl (C1-6) alkyl replacement.At an aspect of this embodiment, R1Quilt Hydroxyisopropyl, particularly 2-hydroxyl acrylate-2-base replace.
In second particular, R1By C1-6Alkyl sulphonyl replaces.At an aspect of this embodiment, R1 Replaced by methyl sulphonyl.
In the 3rd particular, R1It is optionally substituted by halogen.At an aspect of this embodiment, R1Replaced by fluorine.
In the 4th particular, R1By (C1-6) replacement of alkyl sulfide sulfoximide base.In this embodiment one Aspect, R1Replaced by methyl sulfur sulfoximide base.
R1Set point value include hydrogen, bromine, chlorine, cyano group ,-CO2Rd, methoxycarbonyl-ethyl, ethoxycarbonylethyl group, hydroxyl Butynyl, chlorphenyl, hydroxy phenyl, anethane-sulfonyl phenyl, (methyl sulphonyl) aminomethyl phenyl, (methyl sulphonyl) ethyl Phenyl, aminomethyl phenyl, amino isopropyl phenyl, acetylaminomethyl phenyl, acetylphenyl, methoxycarbonyl benzene Base, aminocarbonyl-phenyl, aminosulfonvlphenyl, acetyl-amino sulfonvlphenyl, (double-((trifluoromethyl) (hydroxyl) benzene Base, methoxyl group azelidinyl, methoxypyrrolidinyl, (methoxycarbonyl) (methyl) pyrrolidinyl, (methoxy) pyrrole Cough up alkyl, chloropyridine base, (chloromethyl) pyridine radicals, oxo-piperidine base, (carboxyl) piperidyl, ethoxycarbonyl piperidin base, methyl Sulfonyl piperazinium base, morpholinyl, methyl sulphonyl-1,2,3,6-tetrahydro pyridyl, acetyl group-1,2,3,6-tetrahydro pyridyl, Tert-butoxycarbonyl-1,2,3,6-tetrahydro pyridyl, Methoxycarbonylmethyl-1,2,3,6-tetrahydro pyridyl, benzofuranyl, Thienyl, indyl, pyrazolyl, methylpyrazole base, methyl sulphonyl pyrazolyl, methysulfonylethyl pyrazolyl, dimethyl Pyrazolyl, (methyl) [N-methyl-N-(methyl sulphonyl) amino] pyrazolyl, methylindazole base, dimethyl are differentOxazolyl, hydroxyl Base isopropyl thiazolyl, methylimidazolyl, methylimidazole base, pyridine radicals, THP trtrahydropyranyl pyridine radicals, fluoro-pyridine radicals, cyano group Pyridine radicals, picolyl, (cyano group) (methyl) pyridine radicals, dimethyl pyrazole piperidinyl, cyclopropyl pyridine base, trifluoromethyl pyridine Base, vinylpyridine piperidinyl, hydroxyisopropyl pyridine radicals, hydroxy-methyl pyridine base, methoxypyridine base, (methoxyl group) (methyl) pyrrole Piperidinyl, isopropoxypyrid base, trifluoro ethoxy pyridine base, (methyl)-(trifluoro ethoxy) pyridine radicals, methylsulfonyl pyridine Base, methyl sulphonyl picolyl, oxo pyridine base, (methyl) (oxo)-pyridine radicals, (dimethyl) (oxo) pyridine radicals, Aminopyridine base, dimethylaminopyridine base, dimethylaminopyridine base, methoxyethylamino pyridine radicals, N-(ethoxy)- N-(methyl) amino-pyridine base, Methylsulfonylamino pyridine radicals, [double (methyl sulphonyl) amino] pyridine radicals, carboxyl pyridine Base, quinolyl, hydroxypyridazin base, pyrimidine radicals, isopropylpyrimidin base, fluorine isopropyl-pyrimidine radicals, hydroxyisopropyl pyrimidine radicals, first Epoxide pyrimidine radicals, carboxyl cyclobutoxy group-pyrimidine radicals, methylthiopyrimidine base, methyl sulphonyl pyrimidine radicals, oxo-pyrimidine base, amino Pyrimidine radicals, Dimethylaminopyrimidine base, methoxyethylamino pyrimidine radicals, N-(carboxy ethyl)-N-(methyl) aminopyrimidine base, Carboxyl clopentylamino pyrimidine radicals, carboxycyclopropyl methylaminopyrimidin base, acetoxyl group isopropylpyrimidin base, ethoxy carbonyl Ethyl-pyrimidine base, HYDROXYPYRAZINE base, hydroxyisopropyl pyrazinyl, pyrrolidinylmethyl phenyl, piperizinylmethyl phenyl, pyridine radicals Piperazinyl, Carboxy-cyclohexyl pyrazolyl, carboxycyclohexyl pyridine radicals, cyclopropyl-pyrimidine base, methyl fluoride cyclopropyl-pyrimidine base, second Acylaminomethyl cyclopropyl-pyrimidine base, hydroxymethyl pyrimidine radicals, hydroxycyclobutyl pyrimidine radicals, (methyl) cyclobutyl glycol-phonetic Piperidinyl, carboxyl-cyclopenta pyrimidine radicals, carboxycyclohexyl pyrimidine radicals, (carboxyl) (methyl) cyclohexyl-pyrimidine radicals, (carboxyl) (hydroxyl Base) cyclohexyl pyrimidine radicals, carboxymethyl cyclohexyl-pyrimidine radicals, ethoxy carbonyl cyclohexyl pyrimidine radicals, (methoxycarbonyl) (first Base)-cyclohexyl pyrimidine radicals, (ethoxy carbonyl) (methyl) cyclohexyl pyrimidine radicals, Carboxy-cyclohexyl pyrazinyl, carboxycyclohexyl Methylpyrimidine base, carboxy cyclohex thiazolinyl-pyridine radicals, carboxy cyclohex alkenyl pyrimidine base, ethoxy carbonyl cyclohexenyl group pyrimidine radicals, carboxylic Base bicyclo-[3.1.0] hexyl pyridine radicals, carboxyl bicyclo-[3.1.0] hexenyl pyridine radicals, carboxyl bicyclo-[3.1.0] hexyl are phonetic Piperidinyl, ethoxy carbonyl bicyclo-[3.1.0] hexyl pyrimidine radicals, carboxyl bicyclo-[4.1.0] alkyl-pyrimidinyl group in heptan, carboxyl bicyclo- [2.2.2] octyl pyrimidine radicals, pyrollidinopyridine base, hydroxypyrrole alkyl pyridine base, hydroxy tetrahydro pyranose pyridine radicals, piperazine Piperidinyl pyridine radicals, acetylpiperidinyl pyridine radicals, (carboxyl) (methyl) piperidinopyridine base, [(carboxyl) (methyl)-piperidyl] (fluorine) pyridine radicals, [(carboxyl) (methyl) piperidyl] (chlorine) pyridine radicals, piperazinyl pyridine base, (methyl) (piperazinyl) pyridine radicals, Cyano ethyl piperazinyl pyridine base, trifluoroethyl piperazinyl pyridine base, methylsulfonyl piperazine yl pyridines base, anethane-sulfonyl Ethyl piperazidine yl pyridines base, oxopiperazinyl pyridine radicals, acetylpiperazinyl pyridine radicals, (t-butoxycarbonylpiperazin base) pyridine Base, (t-butoxycarbonylpiperazin base) (methyl) pyridine radicals, methyl piperazine yl pyridines base, carboxymethyl piperazinyl pyridine base, carboxyl Ethyl piperazidine yl pyridines base, ethoxy carbonyl methyl piperazinyl pyridine base, ethoxycarbonylethyl group piperazinyl pyridine base, morpholinyl Pyridine radicals, thio-morpholinyl-pyridine radicals, (tert-butoxycarbonyl)-3,6-dihydropyridine, oxo thio-morpholinyl pyridine radicals, two Oxo thio-morpholinyl pyridine radicals, oxo Diazesuberane base-pyridine radicals, THP trtrahydropyranyl pyrimidine radicals, Replacement of Oxygen by Fluorine heterocycle fourth Yl pyrimidines base, hydroxyl oxygen heterocycle butyl pyrimidine base, hydroxyazetidinium base-pyrimidine radicals, (hydroxyl) (methyl) azelidinyl are phonetic Piperidinyl, (hydroxyl) (trifluoromethyl) azelidinyl pyrimidine radicals, carboxyl azelidinyl pyrimidine radicals, (tert-butoxycarbonyl) (hydroxyl Base) azelidinyl pyrimidine radicals, tetrazole radical azelidinyl pyrimidine radicals, hydroxyl tetrahydrofuran yl pyrimidines base, hydroxypyrrole alkyl Pyrimidine radicals, carboxy-pyrrolidinyl pyrimidine radicals, (carboxyl) (methyl) Pyrrolidyl pyrimidine base, carboxymethyl-Pyrrolidyl pyrimidine base, Ethoxy carbonyl Pyrrolidyl pyrimidine base, fluoro-THP trtrahydropyranyl pyrimidine radicals, hydroxy tetrahydro pyranose pyrimidine radicals, (hydroxyl) dioxy Bridge tetrahydro thiapyran base) pyrimidine radicals, piperidinyl pyrimidine base, dif luoropiperidinyl-pyrimidine radicals, (cyano group) (methyl) piperidinyl pyrimidine base, (hydroxyl) (nitromethyla) piperidyl-pyrimidine radicals, (hydroxyl) (methyl) piperidinyl pyrimidine base, (hydroxyl) (trifluoromethyl)-piperidines Yl pyrimidines base, (hydroxymethyl) (methyl) piperidinyl pyrimidine base, methyl-sulfonylpiperdinyl pyrimidine radicals, oxo-piperidine yl pyrimidines Base, (formoxyl) (methyl)-piperidinyl pyrimidine base, carboxypiperidin yl pyrimidines base, (carboxyl) (fluorine) piperidyl-pyrimidine radicals, (carboxylic Base) (methyl) piperidinyl pyrimidine base, (carboxyl) (ethyl) piperidyl-pyrimidine radicals, (carboxyl) (trifluoromethyl) piperidinyl pyrimidine base, (carboxyl) (hydroxyl)-piperidinyl pyrimidine base, (carboxyl) (hydroxymethyl) piperidinyl pyrimidine base, (carboxyl)-(methoxyl group) piperidyl Pyrimidine radicals, (amino) (carboxyl) piperidinyl pyrimidine base, carboxy-methyl piperidinyl pyrimidine base, methoxycarbonylpiperidin yl pyrimidines base, Ethoxy carbonyl-piperidinyl pyrimidine base, (ethoxy carbonyl) (fluorine) piperidinyl pyrimidine base, (methoxy-carbonyl) (methyl) piperidines Yl pyrimidines base, (ethyl) (methoxycarbonyl) piperidyl-pyrimidine radicals, (isopropyl) (methoxycarbonyl) piperidinyl pyrimidine base, (second Epoxide carbonyl)-(methyl) piperidinyl pyrimidine base, (n-butoxycarbonyl) (methyl) piperidinyl pyrimidine base, (ethoxy carbonyl) (three Methyl fluoride) piperidinyl pyrimidine base, (ethoxy carbonyl)-(hydroxymethyl) piperidinyl pyrimidine base, (methoxyl group) (methoxycarbonyl) Piperidyl-pyrimidine radicals, (carboxyl) (methoxycarbonyl) piperidinyl pyrimidine base, (methyl)-(morpholinyl ethoxy carbonyl) piperidyl Pyrimidine radicals, ethoxy carbonyl methyl piperidyl-pyrimidine radicals, Methylsulfonylamino carbonyl piperazine piperidinyl pyrimidine radicals, Acetylpiperidin Yl pyrimidines base, acetyl-amino-sulfonyl piperidinyl groups pyrimidine radicals, Methoxyamino carbonyl piperazine piperidinyl pyrimidine radicals, tetrazole radical piperidines Yl pyrimidines base, hydroxylDi azoly piperidinyl pyrimidine base, amino-sulfonyl piperidinyl pyrimidine base, piperazinylpyrimidine base, methyl Sulfonyl piperazinium base-pyrimidine radicals, oxopiperazinyl pyrimidine radicals, carboxypiperazinyl pyrimidine radicals, carboxy ethyl-piperazinylpyrimidine base, T-butoxycarbonylpiperazin yl pyrimidines base, tetrazole radical methyl-piperazinyl group pyrimidine radicals, trioxy-hexahydro-[1,2,5] thiadiazoles is also [2,3-a] pyrazinyl pyrimidine radicals, morpholinyl pyrimidine radicals, dimethylated morpholinyl pyrimidine radicals, hydroxymethyl morpholinyl-pyrimidine radicals, carboxylic Base morpholinyl pyrimidine radicals, (carboxyl) (methyl) morpholinyl pyrimidine radicals, carboxymethyl morpholinyl pyrimidine radicals, thio-morpholinyl pyrimidine radicals, Oxo-thiomorpholin yl pyrimidines base, dioxo-thiomorpholinyl pyrimidine radicals, carboxyl azepan yl pyrimidines base, carboxyl oxygen nitrogen Trioxepane base-pyrimidine radicals, oxo Diazesuberane yl pyrimidines base, (oxo Diazesuberane base) (trifluoromethyl) pyrimidine Base, (oxo Diazesuberane base) (methoxyl group) pyrimidine radicals, (methyl) (oxo) Diazesuberane yl pyrimidines base, dioxy Generation-thia Diazesuberane yl pyrimidines base, hydroxyl oxetanylmethoxy pyrazinyl, (carboxyl) (methyl) piperidyl-pyrazinyl, (ethoxy carbonyl) (methyl) piperidyl pyrazinyl, morpholinyl methyl thienyl, morpholinyl ethyl pyrazolyl, isopropyl methyl pyrrole Oxazolyl, carboxyl-3-azabicyclo [3.1.0] hexyl pyridine radicals, carboxyl-3-azabicyclo [3.1.0] hexyl pyridazinyl, carboxylic Base-3-azabicyclo [3.1.0] hexyl pyrimidine radicals, (carboxyl) (methyl)-3-azabicyclo [3.1.0] hexyl pyrimidine radicals, Methoxycarbonyl-3-azabicyclo [3.1.0] hexyl pyrimidine radicals, ethoxy carbonyl-3-azabicyclo [3.1.0] hexyl- Pyrimidine radicals, 2-oxa--5-azabicyclo [2.2.1] heptane yl pyrimidines base, carboxyl-2-oxa--5-azabicyclo-[2.2.1] heptan Alkyl base, carboxyl-3-azabicyclo [3.1.1] heptane yl pyrimidines base, carboxyl-3-azabicyclo [4.1.0] alkylated pyrazole in heptan Piperidinyl, carboxyl-3-azabicyclo [4.1.0] heptane yl pyrimidines base, methoxycarbonyl-3-azabicyclo [4.1.0] heptane base are phonetic Piperidinyl, ethoxy carbonyl-3-azabicyclo-[4.1.0] heptane yl pyrimidines base, (hydroxyl) (methyl) (oxo)-2-oxabicyclo [2.2.2] octyl-pyrimidine radicals, carboxyl-3-azabicyclo [3.2.1] octyl pyrimidine radicals, methoxycarbonyl-3-azabicyclo [3.2.1] octyl pyrimidine radicals, oxo-8-azabicyclo [3.2.1] octyl pyrimidine radicals, ethoxycarbonylmethylene-8-nitrogen Miscellaneous dicyclo [3.2.1] octyl pyrimidine radicals, 3-oxa--8-azabicyclo-[3.2.1] octyl pyrimidine radicals, 3-carboxyl-8-azepine Dicyclo-[3.2.1]-octyl pyrimidine radicals, 3-(Dimethylaminocarbonyl)-8-azabicyclo-[3.2.1] octyl pyrimidine radicals, Oxo-3,6-diazabicyclo [3.2.2] nonyl pyrimidine radicals, 3,7-dioxa-9-azabicyclo [3.3.1]-nonyl are phonetic Piperidinyl, carboxyl-3-oxa--7-azabicyclo [3.3.1] nonyl pyrimidine radicals, carboxyl-5-azaspiro [2.3] hexyl pyrimidine Base, (carboxyl) (methyl)-5-azaspiro [2.3] hexyl pyrimidine radicals, carboxyl-5-azaspiro [2.4] alkyl-pyrimidinyl group in heptan, carboxylic Base-2-azepine spiroheptane yl pyrimidines base, 2-oxa--6-azepine spiroheptane base-pyrimidine radicals, 2-oxa--6-azepine Spiral shell [3.4] octyl pyrimidine radicals, 2-oxa--6-azaspiro [3.5] nonyl-pyrimidine radicals, 2-oxa--7-azaspiro [3.5] nonyl Alkyl base, (dioxo) (methyl)-2,4,8-thriazaspiro [4.5] decyl pyrimidine radicals, 3,6-epimino base (epimino) furo [3.2-b] furyl-pyrimidine radicals, 5-(methyl isophthalic acid H-1,2,4-triazole-3 base) phenyl, xylylenimine Base, (methyl sulphonyl) dihydro-iso indolyl (tetrahydro-thienyl) pyrazolyl, methyl sulfur sulfoximide base phenyl, (imino group) (oxygen Generation) thiazine alkyl, (oxo) thiazine alkyl and (dioxo) thiazine alkyl.R1Other value include cyanoisopropyl-pyrimidine radicals, 3-azabicyclo [3.2.1] octyl pyrimidine radicals, 1H-pyridin-2-ones, (methyl)-1H-pyridin-2-ones, (cyclopropyl)-1H-pyrrole Pyridine-2-ketone, (cyclopropyl) sulfonyl-phenyl, aminosulfonyl-phenyl, (isopropyl) sulfonvlphenyl and (hydroxyl) ethyl ammonia Base sulfonyl-phenyl.R1Appropriate value include bromine, fluoro-THP trtrahydropyranyl pyrimidine radicals, fluoro-oxetanylmethoxy pyrimidine radicals, tetrahydrochysene pyrrole Mutter yl pyridines base, isopropylpyrimidin base, isopropyl methyl pyrazolyl, methyl sulphonyl picolyl, morpholinyl pyrimidine radicals, hydroxyl Base isopropylpyrimidin base, cyclopropyl pyridine base, (methyl) cyclobutyl glycol-pyrimidine radicals, hydroxyisopropyl pyridine radicals, carboxyl-3- Azabicyclo [3.2.1] octyl, anethane-sulfonyl phenyl, hydroxy-methyl pyridine base, methylsulfonyl pyridine base, methyl sulphur Acyl piperazine yl pyridines base, methyl piperazine yl pyridines base, acetylpiperazinyl pyridine radicals, dimethyl pyrazole piperidinyl, methylpyrazole base, Oxo Diazesuberane yl pyrimidines base, piperazinyl pyridine base, pyridine radicals, (carboxyl) (methyl) piperidinyl pyrimidine base, methoxyl group Pyridine radicals, oxo pyridine base, (methyl sulphonyl) aminomethyl phenyl, methyl sulfur sulfoximide base phenyl, (imino group) (oxo) thiazine Alkyl, (oxo) thiazine alkyl, (dioxo) thiazine alkyl, THP trtrahydropyranyl-pyrimidine radicals；2-oxa--7-azaspiro [3.5] nonyl Alkyl base, cyanoisopropyl-pyrimidine radicals, (hydroxyl) oxetanylmethoxy-pyrimidine radicals, fluorine isopropylpyrimidin base, 3,7-dioxy Miscellaneous-9-azabicyclo [3.3.1] nonyl-pyrimidine radicals, 3-azabicyclo [3.2.1] octyl pyrimidine radicals, 1H-pyridin-2-ones, (methyl)-1H-pyridin-2-ones, (cyclopropyl)-1H-pyridin-2-ones, (cyclopropyl) sulfonyl-phenyl, (isopropyl) sulfonyl Phenyl, aminosulfonyl-phenyl and (hydroxyl) ethylaminosulfonyl-phenyl.
R1Example values include bromine, fluoro-THP trtrahydropyranyl pyrimidine radicals, fluoro-oxetanylmethoxy pyrimidine radicals, THP trtrahydropyranyl Pyridine radicals, isopropylpyrimidin base, isopropyl methyl pyrazolyl, methyl sulphonyl picolyl, morpholinyl pyrimidine radicals, hydroxyl are different Propyl group pyrimidine radicals, cyclopropyl pyridine base, (methyl) cyclobutyl glycol-pyrimidine radicals, hydroxyisopropyl pyridine radicals, carboxyl-3-azepine Dicyclo [3.2.1] octyl, anethane-sulfonyl phenyl, hydroxy-methyl pyridine base, methylsulfonyl pyridine base, methyl sulphonyl Piperazinyl pyridine base, methyl piperazine yl pyridines base, acetylpiperazinyl pyridine radicals, dimethyl pyrazole piperidinyl, methylpyrazole base, oxo Diazesuberane yl pyrimidines base, piperazinyl pyridine base, pyridine radicals, (carboxyl) (methyl) piperidinyl pyrimidine base, methoxypyridine Base, oxo pyridine base, (methyl sulphonyl) aminomethyl phenyl, methyl sulfur sulfoximide base phenyl, (imino group) (oxo) thiazine alkyl, (oxo) thiazine alkyl and (dioxo) thiazine alkyl.
Typically, R2Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl or trifluoromethoxy；Or-ORa；Or optionally The C that is replaced1-6Alkyl.
At R2On the exemplary of optionally substituted base include C2-6Alkoxy carbonyl.
At R2On the exemplary of concrete substituent group include ethoxy carbonyl.
In the first embodiment, R2Represent hydrogen.In second embodiment, R2Represent halogen.In this embodiment An aspect, R2Represent fluorine.At another aspect of this embodiment, R2Represent chlorine.In a third embodiment, R2Generation Table cyano group.In the 4th embodiment, R2Represent nitro.In the 5th embodiment, R2Representation hydroxy.The 6th reality Execute in scheme, R2Represent trifluoromethyl.In the 7th embodiment, R2Represent trifluoromethoxy.The 8th embodiment In, R2Representative-ORa.In the 9th embodiment, R2Represent optionally substituted C1-6Alkyl.In this embodiment one Aspect, R2Represent unsubstituted methyl.At another aspect of this embodiment, R2Represent unsubstituted ethyl.Real at this Execute another aspect of scheme, R2Represent mono-substituted methyl or mono-substituted ethyl.
R2Representative value include hydrogen, fluorine, chlorine, trifluoromethyl, trifluoromethoxy ,-ORa, methyl and ethoxycarbonylethyl group.
R2Particular value include hydrogen and fluorine.
Typically, R3Represent hydrogen, halogen or C1-6Alkyl.
In the first embodiment, R3Represent hydrogen.
In second embodiment, R3Represent halogen.At an aspect of this embodiment, R3Represent fluorine.
In a third embodiment, R3Represent C1-6Alkyl.At an aspect of this embodiment, R3Represent unsubstituted C1-6Alkyl.At the second aspect of this embodiment, R3Represent substituted C1-6Alkyl.A certain party in this embodiment Face, R3Represent methyl.At another particular aspects of this embodiment, R3Represent ethyl.
In one particular embodiment, R3Represent hydrogen.
Typically, R4Represent hydrogen, halogen or C1-6Alkyl.
In the first embodiment, R4Represent hydrogen.
In second embodiment, R4Represent halogen.At an aspect of this embodiment, R4Represent fluorine.
In a third embodiment, R4Represent C1-6Alkyl.At an aspect of this embodiment, R4Represent unsubstituted C1-6Alkyl.At the second aspect of this embodiment, R4Represent substituted C1-6Alkyl.A certain party in this embodiment Face, R4Represent methyl.At another particular aspects of this embodiment, R4Represent ethyl.
In one particular embodiment, R4Represent hydrogen.In another particular, R4Represent fluorine.
Typically, R5aRepresent hydrogen, hydroxyl, halogen, cyano group, trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-(CO) NRcRd、-NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)、-S(O)2(N-Rd)、-ORa、-C(O)2RdOr- O(CO)-Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heteroaryl, any one in described group can be optionally It is substituted with one or more substituents.
Typically, R5aRepresent hydrogen, hydroxyl, halogen or trifluoromethyl；Or-NRbRc、S(O)2Ra、-ORaOr O-(CO)-Rd；Or C1-6Alkyl, any one in described group can be optionally substituted.
At R5aOn the suitable example of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, hydroxyl, trifluoromethyl, C1-6Alkyl, C1-6Alkoxyl, C2-6Alkyl-carbonyl, C2-6Alkoxy carbonyl, (hydroxyl) C1-6Alkane Base, (C3-7) cycloalkyl, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, two (C1-6) alkyl amino-carbonyl, oxygen Generation and carboxyl.
At R5aOn the exemplary of concrete substituent group include that one, two or three is independently selected from following replacement Base: fluorine, chlorine, methyl fluoride, fluorine isopropyl, cyano group, cyano ethyl, nitromethyla, methyl, ethyl, isopropyl, isopropyl methyl, Trifluoromethyl, trifluoroethyl, vinyl, hydroxyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, isopropoxy, three fluoro-ethoxies Base, carboxyl cyclobutoxy group, methyl mercapto, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl, oxo, amino, ammonia Ylmethyl, amino isopropyl, methylamino, dimethylamino, methoxyethylamino, N-(ethoxy)-N-(methyl) amino, Acetylaminomethyl, Methylsulfonylamino, N-methyl-N-(methyl sulphonyl) amino, double (methyl sulphonyl) amino, N- (carboxy ethyl)-N-(methyl) amino, carboxyl clopentylamino, carboxycyclopropyl methylamino, formoxyl, acetyl group, acetyl Epoxide isopropyl, carboxyl, carboxymethyl, carboxy ethyl, methoxycarbonyl, ethoxy carbonyl, n-butoxycarbonyl, tert-butoxy carbonyl Base, Methoxycarbonylmethyl, ethoxy-carbonyl methyl, ethoxycarbonylethyl group, morpholinyl ethoxy carbonyl, ethoxy carbonyl- Methylene, Methylsulfonylamino carbonyl, acetyl-amino sulfonyl, Methoxyamino-carbonyl, tetrazole radical, tetrazole radical methyl, HydroxylDi azoly, amino carbonyl, amino-sulfonyl, methyl sulfur sulfoximide base and (methyl) (N-methyl) sulfur sulfoximide base.
In the first embodiment, R5aRepresent hydrogen.In second embodiment, R5aRepresentation hydroxy.The 3rd reality Execute in scheme, R5aRepresent halogen.At an aspect of this embodiment, R5aRepresent fluorine.In the 4th embodiment, R5aGeneration Table trifluoromethyl.In the 5th embodiment, R5aRepresentative-NRbRc.At an aspect of this embodiment, R5aRepresentative-NH2。 In the 6th embodiment, R5aRepresentative-NRcC(O)Rd.In the 7th embodiment, R5aRepresent-C (O)-NRcRd.? In eight embodiments, R5aRepresent-NHS (O)2Re.In the 9th embodiment, R5aRepresentative-S-Ra.The tenth embodiment party In case, R5aRepresent-S (O)-Ra.In the 11st embodiment, R5aRepresent-S (O)2Ra.A spy in this embodiment Determine aspect, R5aRepresent-S (O)2-CH3.In the 12nd embodiment, R5aRepresent-S (O) (N-Rd)Ra.The 13rd reality Execute in scheme, R5aRepresent-S (O)2(N-Rd).In the 14th embodiment, R5aRepresentative-ORa.In this embodiment one Individual aspect, RaIt is the C being optionally substituted1-6Alkyl.At the second aspect of this embodiment, RaIt it is the virtue being optionally substituted Base.At the third aspect of this embodiment, RaIt it is the heteroaryl being optionally substituted.In the 15th embodiment, R5aGeneration Table-O-(CO)-Rd.At a particular aspects of this embodiment, R5aRepresent-O-(CO)-CH3.The 16th embodiment In, R5aRepresent-C (O)-ORd.In the 17th embodiment, R5aRepresent optionally substituted C1-6Alkyl.This embodiment party One aspect of case, R5aRepresent substituted C1-6Alkyl.At the second aspect of this embodiment, R5aRepresent unsubstituted C1-6Alkane Base.At a particular aspects of this embodiment, R5aRepresent methyl.In the 18th embodiment, R5aRepresent optionally by Substituted C2-6Alkynyl.In nineteen embodiment, R5aRepresent the heteroaryl being optionally substituted.
In the 20th embodiment, R5aRepresent the aryl being optionally substituted.In the 21st embodiment, R5aRepresent the C being optionally substituted2-6Thiazolinyl.
In the 22nd embodiment, R5aRepresent cyano group.
Generally, R5bRepresent hydrogen, hydroxyl, halogen, cyano group, trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-(CO)NRcRd、- NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)、-S(O)2(N-Rd)、-ORa、-C(O)2RdOr-O (CO)- Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl, heteroaryl, any one in described group can be optionally by one Or multiple substituent group replaces.
Typically, R5bRepresent hydrogen, hydroxyl, halogen or trifluoromethyl；Or-NRbRc、S(O)2Ra、-ORaOr O-(CO)-Rd；Or C1-6Alkyl, any one in described group can be optionally substituted.
At R5bOn the suitable example of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, hydroxyl, trifluoromethyl, C1-6Alkyl, C1-6Alkoxyl, C2-6Alkyl-carbonyl, C2-6Alkoxy carbonyl, (hydroxyl) C1-6Alkane Base, (C3-7) cycloalkyl, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, two (C1-6) alkyl amino-carbonyl, oxygen Generation and carboxyl.
At R5bOn the exemplary of concrete substituent group include that one, two or three is independently selected from following replacement Base: fluorine, chlorine, methyl fluoride, fluorine isopropyl, cyano group, cyano ethyl, nitromethyla, methyl, ethyl, isopropyl, isopropyl methyl, Trifluoromethyl, trifluoroethyl, vinyl, hydroxyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, isopropoxy, three fluoro-ethoxies Base, carboxyl cyclobutoxy group, methyl mercapto, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl, oxo, amino, ammonia Ylmethyl, amino isopropyl, methylamino, dimethylamino, methoxyethylamino, N-(ethoxy)-N-(methyl) amino, Acetylaminomethyl, Methylsulfonylamino, N-methyl-N-(methyl sulphonyl) amino, double (methyl sulphonyl) amino, N- (carboxy ethyl)-N-(methyl) amino, carboxyl clopentylamino, carboxycyclopropyl methylamino, formoxyl, acetyl group, acetyl Epoxide isopropyl, carboxyl, carboxymethyl, carboxy ethyl, methoxycarbonyl, ethoxy carbonyl, n-butoxycarbonyl, tert-butoxy carbonyl Base, Methoxycarbonylmethyl, ethoxy-carbonyl methyl, ethoxycarbonylethyl group, morpholinyl ethoxy carbonyl, ethoxy carbonyl- Methylene, Methylsulfonylamino carbonyl, acetyl-amino sulfonyl, Methoxyamino-carbonyl, tetrazole radical, tetrazole radical methyl, HydroxylDi azoly, amino carbonyl, amino-sulfonyl, methyl sulfur sulfoximide base and (methyl) (N-methyl) sulfur sulfoximide base.
In the first embodiment, R5bRepresent hydrogen.In second embodiment, R5bRepresentation hydroxy.The 3rd reality Execute in scheme, R5bRepresent halogen.At an aspect of this embodiment, R5bRepresent fluorine.In the 4th embodiment, R5bGeneration Table trifluoromethyl.In the 5th embodiment, R5bRepresentative-NRbRc.At an aspect of this embodiment, R5bRepresentative-NH2。 In the 6th embodiment, R5bRepresentative-NRcC(O)Rd.In the 7th embodiment, R5bRepresent-C (O)-NRcRd.? In eight embodiments, R5bRepresent-NHS (O)2Re.In the 9th embodiment, R5aRepresentative-S-Ra.The tenth embodiment party In case, R5bRepresent-S (O)-Ra.In the 11st embodiment, R5bRepresent-S (O)2Ra.A spy in this embodiment Determine aspect, R5bRepresent-S (O)2-CH3.In the 12nd embodiment, R5bRepresent-S (O) (N-Rd)Ra.The 13rd reality Execute in scheme, R5bRepresent-S (O)2(N-Rd).In the 14th embodiment, R5bRepresentative-ORa.In this embodiment one Individual aspect, RaIt is C1-6Alkyl.At the second aspect of this embodiment, RaIt it is aryl.At the third aspect of this embodiment, RaIt is Heteroaryl.In the 15th embodiment, R5bRepresent-O-(CO)-Rd.At a particular aspects of this embodiment, R5bGeneration Table-O-(CO)-CH3.In the 16th embodiment ,-C (O)-ORd.In the 17th embodiment, R5bRepresent optionally The substituted C in ground1-6Alkyl.At an aspect of this embodiment, R5bRepresent substituted C1-6Alkyl.In this embodiment second Aspect, R5bRepresent unsubstituted C1-6Alkyl.At a particular aspects of this embodiment, R5bRepresent methyl.At the 18th In embodiment, R5bRepresent the C being optionally substituted2-6Alkynyl.In nineteen embodiment, R5bRepresent and optionally taken The heteroaryl in generation.In the 20th embodiment, R5bRepresent the aryl being optionally substituted.The 21st embodiment In, R5bRepresent the C being optionally substituted2-6Thiazolinyl.In the 22nd embodiment, R5bRepresent cyano group.
Specifically, R5bRepresent hydrogen or methyl.
In an alternative embodiment, R5aAnd R5bCarbonyl, thiocarbonyl or-C is represented together with the carbon being connected with them =N-OH.
At an aspect of this alternate embodiment, R5aAnd R5bCarbonyl is represented together with the carbon being connected with them.
At the second aspect of this alternate embodiment, R5aAnd R5bThiocarbonyl is represented together with the carbon being connected with them.
At another aspect of this alternate embodiment, R5aAnd R5b-C=N-OH is represented together with the carbon being connected with them.
R5aParticular value include hydrogen, hydroxyl, fluorine, trifluoromethyl ,-N (CH3)2、-NH(CO)CH3、-SO2-CH3、-O- (CO)-CH3, methyl, methoxyl group, (hydroxyl) ethyoxyl, (hydroxyl) propoxyl group and 2-OXo-1-pyrrolidine base-.
R5aSet point value include hydrogen, hydroxyl, fluorine, trifluoromethyl ,-N (CH3)2、-NH(CO)CH3、-SO2-CH3、-O- (CO)-CH3, methyl and methoxyl group.
R5bSet point value include hydrogen, hydroxyl, fluorine, trifluoromethyl ,-N (CH3)2、-NH(CO)CH3、-SO2-CH3、-O- (CO)-CH3, methyl and methoxyl group.
In one particular embodiment, R5aAs defined above and R5bRepresent hydrogen.Specific of this embodiment Aspect, R5aIt it is hydroxyl.
In another particular, R5aAs defined above and R5bRepresent C1-4Alkyl, preferably methyl.Real at this Execute a particular aspects of scheme, R5aIt it is hydroxyl.
Generally, R6Represent hydrogen, hydroxyl, halogen, cyano group, trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-NHS(O)2Re、-S (O)2Ra、-S(O)(N-Rd)RaOr-O-(CO)-Rd；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heteroaryl, described base Any one in group can optionally be substituted with one or more substituents.
Typically, R6Represent hydrogen, hydroxyl, halogen or trifluoromethyl.
In one particular embodiment, R6Represent hydrogen.
In an alternative embodiment, R6C is formed together with the carbon being connected with them with Y3-7Cycloalkyl.
In another alternate embodiment, R6C is formed together with the carbon being connected with them with Y3-7Heterocyclylalkyl.At root According to a particular aspects of this embodiment, R6Dihydrobenzofuranes is formed together with the carbon being connected with them with Y.According to being somebody's turn to do Second particular aspects of embodiment, R63H-benzofuranone is formed together with the carbon being connected with them with Y.According to being somebody's turn to do 3rd particular aspects of embodiment, R6Xylylenimine is formed together with the carbon being connected with them with Y.According to this enforcement 4th particular aspects of scheme, R6Xylylenimine ketone is formed together with the carbon being connected with them with Y.
At Ra、Rb、Rc、RdOr ReGo up or at heterocyclic moiety-NRbRcOn the exemplary of suitable substituent include halogen, C1-6Alkyl, C1-6Alkoxyl, difluoro-methoxy, trifluoromethoxy, C1-6Alkoxyl (C1-6) alkyl, C1-6Alkylthio group, C1-6Alkyl Sulfinyl, C1-6Alkyl sulphonyl, hydroxyl, hydroxyl (C1-6) alkyl, amino (C1-6) alkyl, cyano group, trifluoromethyl, oxo, C2-6Alkyl-carbonyl, carboxyl, C2-6Alkoxy carbonyl, C2-6Alkyl-carbonyl epoxide, amino, C1-6Alkyl amino, two (C1-6) alkyl ammonia Base, phenyl amino, pyridinylamino, C2-6Alkyl-carbonyl-amino, C2-6Alkyl-carbonyl-amino (C1-6) alkyl, C2-6Alkoxy carbonyl Amino, C1-6Alkyl sulfonyl-amino, amino carbonyl, C1-6Alkyl amino-carbonyl and two (C1-6) alkyl amino-carbonyl.At RaOn Other example of optionally substituted base includes 2-OXo-1-pyrrolidine base.
At Ra、Rb、Rc、RdOr ReGo up or at heterocyclic moiety-NRbRcOn the exemplary of concrete substituent group include fluorine, chlorine, Bromine, methyl, ethyl, isopropyl, methoxyl group, isopropoxy, difluoro-methoxy, trifluoromethoxy, methoxy, methyl mercapto, Ethylmercapto group, methylsulfinyl, methyl sulphonyl, hydroxyl, hydroxymethyl, ethoxy, amino methyl, cyano group, trifluoromethyl, oxygen Generation, acetyl group, carboxyl, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, acetoxyl group, amino, methylamino, ethyl Amino, dimethylamino, phenyl amino, pyridinylamino, acetyl-amino, tertbutyloxycarbonylamino, acetyl-amino first Base, Methylsulfonylamino, amino carbonyl, methylaminocarbonyl and Dimethylaminocarbonyl.
Suitably, RaRepresent C1-6Alkyl, aryl (C1-6) alkyl or heteroaryl (C1-6) alkyl, arbitrary in described group Individual can optionally be substituted with one or more substituents.
RaSet point value include methyl, ethyl, benzyl and isoindolyl propyl group, any one in described group can be optional Be substituted with one or more substituents.RaOther value include propyl group.
At RaOn the selected example of suitable substituent include C1-6Alkoxyl and oxo.At RaOn its of suitable substituent Its example includes 2-OXo-1-pyrrolidine base.
At RaOn the suitable example of concrete substituent group include methoxyl group, oxo, hydroxyl and 2-OXo-1-pyrrolidine base.
At RaOn the selected example of concrete substituent group include methoxyl group and oxo.
In one embodiment, RaRepresent optionally substituted C1-6Alkyl.At an aspect of this embodiment, RaReason Represent unsubstituted C with thinking1-6Alkyl, particularly methyl.At another aspect of this embodiment, RaRepresent ideally and take The C in generation1-6Alkyl, such as methoxy ethyl.In another embodiment, RaRepresent optionally substituted aryl.In this enforcement One aspect of scheme, RaRepresent unsubstituted aryl, particularly phenyl.At another aspect of this embodiment, RaRepresent Mono-substituted aryl, particularly aminomethyl phenyl.In another embodiment, RaRepresent optionally substituted aryl (C1-6) alkane Base, represents unsubstituted aryl (C ideally1-6) alkyl, particularly benzyl.In another embodiment, RaRepresent optionally The substituted heteroaryl in ground.In another embodiment, RaRepresent optionally substituted heteroaryl (C1-6) alkyl, such as dioxy For isoindolyl propyl group.In another embodiment, RaRepresent C3-7Cycloalkyl.In another embodiment, RaRepresent C3-7 Heterocyclylalkyl.
RaOccurrence include methyl, methoxy ethyl, benzyl and dioxoisoindole base-propyl group.RaOther concrete Value includes (hydroxyl) ethyl, (hydroxyl) propyl group and 2-OXo-1-pyrrolidine base-ethyl.
At a particular aspects, RbRepresent hydrogen or trifluoromethyl；Or C1-6Alkyl, C3-7Cycloalkyl, C3-7Cycloalkyl (C1-6) Alkyl, aryl, aryl (C1-6) alkyl, C3-7Heterocyclylalkyl, C3-7Heterocyclylalkyl (C1-6) alkyl, heteroaryl or heteroaryl (C1-6) Alkyl, any one in described group can optionally be substituted with one or more substituents.
RbSet point value include hydrogen；Or C1-6Alkyl, aryl (C1-6) alkyl, C3-7Heterocyclylalkyl or C3-7Heterocyclylalkyl (C1-6) alkyl, any one in described group can optionally be substituted with one or more substituents.
RbRepresentative value include hydrogen and C1-6Alkyl.
Exemplarily, RbRepresent hydrogen or trifluoromethyl；Or methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, 2-methyl-prop Base, the tert-butyl group, amyl group, hexyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Cvclopropvlmethvl, cyclobutylmethyl, cyclopenta Methyl, cyclohexyl methyl, phenyl, benzyl, phenylethyl, azelidinyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, Piperidyl, homopiperidinyl, morpholinyl, azetidin ylmethyl, oxolane ylmethyl, pyrrolidinylmethyl, pyrrolidinyl second Base, pyrrolidinylpropyl, thiazolidinylmethyl, imidazolidinyl ethyl, piperidino methyl, piperidinoethyl, tetrahydric quinoline group first Base, piperazinopropyl, morpholinyl methyl, morpholinyl ethyl, morpholinyl propyl, pyridine radicals, indolylinethyl, pyrazolmethyl, Pyrazolylethyl, imidazolyl methyl, imidazolylethyl, benzimidazole ylmethyl, triazolyl methyl, pyridylmethyl or pyridine radicals Ethyl, any one in described group can optionally be substituted with one or more substituents.
RbRepresentative value include hydrogen；Or methyl, ethyl, n-pro-pyl, benzyl, pyrrolidinyl or morpholinyl propyl, described Any one in group can optionally be substituted with one or more substituents.
At RbOn the selected example of suitable substituent include C1-6Alkoxyl, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, hydroxyl, cyano group, C2-6Alkoxy carbonyl, two-(C1-6) alkyl amino and C2-6Alkoxycarbonyl amino.
At RbOn the selected example of concrete substituent group include methoxyl group, methyl mercapto, methylsulfinyl, sulfonyloxy methyl Base, hydroxyl, cyano group, tert-butoxycarbonyl, dimethylamino and tertbutyloxycarbonylamino.
RbOccurrence include hydrogen, methyl, methoxy ethyl, methylmercaptoethyl, methylsulfinylethane groups, sulfonyloxy methyl Base ethyl, ethoxy, cyano ethyl, dimethylarnino-ethyl, tertbutyloxycarbonylamino ethyl, dihydroxypropyl, benzyl, Pyrrolidinyl, butyloxycarbonyl pyrrolidine base and morpholinyl propyl.
In one embodiment, RbRepresent hydrogen.In another embodiment, RbRepresent C1-6Alkyl, particularly methyl.
RcSet point value include hydrogen；Or C1-6Alkyl, C3-7Cycloalkyl or C3-7Heterocyclylalkyl, any one in described group Can optionally be substituted with one or more substituents.
At a particular aspects, RcRepresent hydrogen, C1-6Alkyl or C3-7Cycloalkyl.
RcRepresentative value include hydrogen；Or methyl, cyclobutyl, cyclopenta, cyclohexyl, THP trtrahydropyranyl and piperidyl, institute State any one in group can optionally be substituted with one or more substituents.
At RcOn the selected example of suitable substituent include C2-6Alkyl-carbonyl and C2-6Alkoxy carbonyl.
At RcOn the selected example of concrete substituent group include acetyl group and tert-butoxycarbonyl.
RcOccurrence include hydrogen, methyl, cyclobutyl, cyclopenta, cyclohexyl, THP trtrahydropyranyl, acetylpiperidinyl and Tert-butoxycarbonylpiperidine base.
Suitably, RcRepresent hydrogen or C1-6Alkyl.In one embodiment, RcIt is hydrogen.In another embodiment, Rc Represent C1-6Alkyl, particularly methyl or ethyl, particularly methyl.In another embodiment, RcRepresent C3-7Cycloalkyl, example Such as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
Alternatively, partly-NRbRcCan suitably represent azetidine-1-base, pyrrolidin-1-yl,Oxazolidine- 3-base, differentOxazolidine-2-base, Thiazolidine-3-base, isothiazolidine-2-base, piperidin-1-yl, morpholine-4-base, thiomorpholine-4- Base, piperazine-1-base, high piperidin-1-yl, high morpholine-4-base or homopiperazine-1-base, (imino group) (oxo) thiazan-4-base, (oxo) thiazan-4-base or (dioxo) thiazan-4-base, any one in described group can be optionally by one or many Individual substituent group replaces.
At heterocyclic moiety-NRbRcOn the selected example of suitable substituent include C1-6Alkyl, C1-6Alkyl sulphonyl, hydroxyl Base, hydroxyl (C1-6) alkyl, amino (C1-6) alkyl, cyano group, oxo, C2-6Alkyl-carbonyl, carboxyl, C2-6Alkoxy carbonyl, amino, C2-6Alkylcarbonyl-amino, C2-6Alkyl-carbonyl-amino (C1-6) alkyl, C2-6Alkoxycarbonyl amino, C1-6Alkyl-sulfonyl base ammonia Base and amino carbonyl.
At heterocyclic moiety-NRbRcOn the selected example of concrete substituent group include methyl, methyl sulphonyl, hydroxyl, hydroxyl Methyl, amino methyl, cyano group, oxo, acetyl group, carboxyl, ethoxy carbonyl, amino, acetyl-amino, acetyl-amino first Base, t-butoxy-carbonyl amino, Methylsulfonylamino and amino carbonyl.
Heterocyclic moiety-NRbRcOccurrence include azetidine-1-base, hydroxy azetidine-1-base, hydroxymethyl Azetidine-1-base, (hydroxyl) (hydroxymethyl) azetidine-1-base, Aminomethvl-azetidine-1-base, cyano group Azetidine-1-base, carboxyl azetidine-1-base, aminoazetidine-1-base, amino carbonyl azetidine-1- Base, pyrrolidin-1-yl, aminomethyl pyrrolidine-1-base, oxo-pyrrolidine-1-base, acetylaminomethyl pyrrolidin-1-yl, Tertbutyloxycarbonylamino pyrrolidin-1-yl, oxo-Oxazolidine-3-base, hydroxyl are differentOxazolidine-2-base, Thiazolidine-3-base, Oxothiazolidin-3-base, Dioxo-isothiazolidin-2-base, piperidin-1-yl, hydroxy piperidine-1-base, hydroxymethylpiperidine-1- Base, amino piperidine-1-base, acetyl-amino piperidin-1-yl, tertbutyloxycarbonylamino piperidin-1-yl, Methylsulfonylamino Piperidin-1-yl, morpholine-4-base, piperazine-1-base, methylpiperazine-1-yl, methylsulfonyl piperazine-1-base, oxypiperazin-1- Base, Acetylpiperazine-1-base, ethoxycarbonylpiperazine-1-base, oxo homopiperazine-1-base, (imino group) (oxo) thiazan- 4-base, (oxo) thiazan-4-base and (dioxo) thiazan-4-base.
Suitably, RdRepresent hydrogen；Or C1-6Alkyl, aryl or heteroaryl, any one in described group can optionally by One or more substituent groups replace.
RdThe selected example of desired value include hydrogen, methyl, ethyl, isopropyl, 2-methyl-propyl, the tert-butyl group, cyclopropyl, Cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazole radicals and thiazolyl, any one in described group can be optionally by one Or multiple substituent group replaces.
At RdOn the selected example of suitable substituent include halogen, C1-6Alkyl, C1-6Alkoxyl, oxo, C2-6Alkyl oxycarbonyl Base epoxide and two (C1-6) alkyl amino.
At RdOn the selected example of concrete substituent group include fluorine, methyl, methoxyl group, oxo, acetoxyl group and dimethyl Amino.
In one embodiment, RdRepresent hydrogen.In another embodiment, RdRepresent optionally substituted C1-6Alkane Base.At an aspect of this embodiment, RdRepresent unsubstituted C ideally1-6Alkyl, such as methyl, ethyl, isopropyl, 2-methyl-propyl or the tert-butyl group, particularly methyl.At another aspect of this embodiment, RdRepresent substituted C ideally1-6 Alkyl, the most substituted methyl or substituted ethyl, including acetoxy-methyl, dimethylaminomethyl and trifluoroethyl.
In another embodiment, RdRepresent optionally substituted aryl.At an aspect of this embodiment, RdGeneration The unsubstituted aryl of table, particularly phenyl.At another aspect of this embodiment, RdRepresent mono-substituted aryl, especially It it is aminomethyl phenyl.At another aspect of this embodiment, RdRepresent dibasic aryl, such as Dimethoxyphenyl.
In another embodiment, RdRepresent optionally substituted heteroaryl, such as thienyl, chlorothiophene base, methyl Thienyl, methylimidazolyl or thiazolyl.In another embodiment, RdRepresent optionally substituted C3-7Cycloalkyl, such as Cyclopropyl or cyclobutyl.
In another embodiment, RdRepresent optionally substituted C3-7Heterocyclylalkyl, such as thiazolidinyl or oxo- Thiazolidinyl.
RdThe selected example of occurrence include hydrogen, methyl, acetoxy-methyl, dimethylaminomethyl, ethyl, three Fluoro ethyl, isopropyl, 2-methyl-propyl, the tert-butyl group, cyclopropyl, cyclobutyl, phenyl, Dimethoxyphenyl, thiazolidinyl, oxo Thiazolidinyl, thienyl, chlorothiophene base, methylthiophene base, methylimidazolyl and thiazolyl.
RdThe object lesson of set point value include hydrogen and methyl.
Suitably, ReRepresent C1-6Alkyl or aryl, any one in described group can optionally be taken by one or more Replace for base.
At ReOn the selected example of suitable substituent include C1-6Alkyl, particularly methyl.
In one embodiment, ReRepresent optionally substituted C1-6Alkyl, represents unsubstituted C ideally1-6Alkane Base, such as methyl or propyl group, particularly methyl.In another embodiment, ReRepresent optionally substituted aryl.Real at this Execute an aspect of scheme, ReRepresent unsubstituted aryl, particularly phenyl.At another aspect of this embodiment, ReGeneration The substituted aryl of list, particularly aminomethyl phenyl.In another embodiment, ReRepresent optionally substituted heteroaryl.
ReSet point value include methyl, propyl group and aminomethyl phenyl.
One subclass of the compound according to the present invention by the compound of formula (IIA) and its N-oxide and its pharmaceutically Acceptable salt and solvate and its glucuronide and its eutectic represent:
Wherein
X、Y、R1、R2、R3、R4、R5a、R5bAnd R6As defined above.
One specific subgroup of the compound of formula (IIA) above by the compound of formula (IIB) and its N-oxide and its Pharmaceutically acceptable salt and solvate and its glucuronide and its eutectic represent:
Wherein
R1Represent halogen or cyano group；Or C1-6Alkyl, C2-6Alkynyl, aryl, C3-7Heterocyclylalkyl, C3-7Heterocycloalkenyl, heteroaryl Base, (C3-7) Heterocyclylalkyl (C1-6) alkyl-aryl-group-, heteroaryl (C3-7) Heterocyclylalkyl-, (C3-7) cycloalkyl-heteroaryl-, (C3-7) cycloalkyl-(C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl-heteroaryl-, (C3-7) Heterocyclylalkyl-heteroaryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-heteroaryl-, (C4-9) miscellaneous Bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl-, any one in described group can be optionally by one Or multiple substituent group replaces；
R2Represent hydrogen, halogen, cyano group, trifluoromethyl；Or the C being optionally substituted1-6Alkyl；
X represents oxygen atom or sulphur atom；Or-S (O) ,-N-Rd；Or the straight or branched C being optionally substituted1-4Alkylidene Chain；
R5aRepresent hydrogen, hydroxyl, halogen, cyano group or trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-(CO)NRcRd、-NHS (O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)、-S(O)2(N-Rd)、-ORa、-C(O)2RdOr-O (CO)- Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl, heteroaryl, any one in described group can be optionally by one Or multiple substituent group replaces；And
R5bRepresent hydrogen, hydroxyl, halogen, cyano group or trifluoromethyl；Or C1-6Alkyl, any one in described group can be appointed Selection of land is substituted with one or more substituents；Or
R5aAnd R5bCarbonyl, thiocarbonyl or-C=N-OH is represented together with the carbon being connected with them；And
Y、Ra、Rb、RcAnd RdCompound as mentioned above for formula (I) is defined.
May reside in R1、R2、R5aAnd R5bOn the example of optionally substituted base include that one, two or three is selected independently Substituent group from following: halogen, halo-(C1-6) alkyl, cyano group, cyano group (C1-6) alkyl, nitro, nitro (C1-6) alkyl, C1-6 Alkyl, (C3-7) cycloalkyl, difluoromethyl, trifluoromethyl, two fluoro ethyls, trifluoroethyl, C2-6Thiazolinyl, hydroxyl, hydroxyl (C1-6) alkane Base, C1-6Alkoxyl, difluoro-methoxy, trifluoromethoxy, trifluoro ethoxy, carboxyl (C3-7) cycloalkyl-epoxide, C1-3Alkylidene Two epoxides, C1-6Alkoxyl (C1-6) alkyl, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphur Acyl group (C1-6) alkyl, oxo, amino, amino (C1-6) alkyl, C1-6Alkyl-amino, two (C1-6) alkyl amino, hydroxyl (C1-6) Alkyl amino, C1-6Alkoxyamino, (C1-6) alkoxyl-(C1-6) alkyl amino, [(C1-6) alkoxyl] (hydroxyl) (C1-6) alkyl ammonia Base, [(C1-6) alkylthio group] (hydroxyl)-(C1-6) alkyl amino, N-[(C1-6) alkyl]-N-[hydroxyl (C1-6) alkyl] amino, two (C1-6) alkyl amino-(C1-6) alkyl amino, N-[two (C1-6) alkyl amino (C1-6) alkyl]-N-[hydroxyl (C1-6) alkyl] ammonia Base, hydroxyl (C1-6) alkyl (C3-7) cycloalkyl amino, (hydroxyl) [(C3-7) cycloalkyl (C1-6) alkyl] amino, (C3-7) heterocycle alkane Base (C1-6) alkyl amino, oxo (C3-7) Heterocyclylalkyl (C1-6) alkyl amino, (C1-6) miscellaneous alkyl aryl amino, heteroaryl (C1-6) alkyl amino, (C1-6) miscellaneous alkyl aryl (C1-6) alkyl-amino, C2-6Alkyl-carbonyl-amino, N-[(C1-6) alkyl]-N- [(C2-6) alkyl-carbonyl] amino, (C2-6) alkyl-carbonylamino (C1-6) alkyl, C3-6Alkenylcarbonylamino, double [(C3-6) thiazolinyl Carbonyl] amino, N-[(C1-6) alkyl]-N-[(C3-7) naphthene base carbonyl] amino, C2-6Alkoxycarbonyl amino, C2-6Alkoxyl carbonyl Base (C1-6) alkyl amino, C1-6Alkyl amino-carbonyl-amino, C1-6Alkylsulfonyl-amino, N-[(C1-6) alkyl]-N-[(C1-6) Alkyl sulphonyl] amino, double [(C1-6) alkyl sulphonyl] amino, N-[(C1-6) alkyl]-N-[carboxyl (C1-6) alkyl] amino, Carboxyl (C3-7) cycloalkyl amino, carboxyl-(C3-7) cycloalkyl (C1-6) alkyl amino, formoxyl, C2-6Alkyl-carbonyl, (C3-7) ring Alkyl-carbonyl, phenylcarbonyl group, (C2-6) alkyl-carbonyl epoxide (C1-6) alkyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxyl carbonyl Base, C2-6Alkoxy carbonyl (C1-6) alkyl, morpholinyl (C1-6) alkoxy carbonyl, C2-6Alkoxy carbonyl methylene, carboxylic acid electronics Isostere or prodrug moiety Ω ,-(C1-6) alkyl-Ω, amino carbonyl, C1-6Alkyl amino-carbonyl, hydroxyl (C1-6) alkyl amino- Carbonyl, two (C1-6) alkyl amino-carbonyl, amino carbonyl (C1-6) alkyl, amino-sulfonyl, two (C1-6) alkyl amino sulfonyl, (C1-6) alkyl sulfide sulfoximide base, [(C1-6) alkyl] [N-(C1-6) alkyl]-sulfur sulfoximide base and heteroaryl.At R1、R2、R5aWith R5bOn other example of optionally substituted base include (C3-7) cycloalkyl-sulfonyl and hydroxyl (C1-6) alkyl amino sulfonyl.
At R1、R2、R5aAnd R5bOn the example of concrete substituent group include fluorine, chlorine, bromine, methyl fluoride, fluorine isopropyl, cyano group, Cyano ethyl, nitro, nitromethyla, methyl, ethyl, isopropyl, isobutyl group, the tert-butyl group, difluoromethyl, trifluoromethyl, difluoro Ethyl, trifluoro ethyl, vinyl, hydroxyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, isopropoxy, difluoro-methoxy, three Fluorine methoxyl group, trifluoro ethoxy, carboxyl cyclobutoxy group, methylene-two epoxide, ethylene epoxide, methoxy, methoxyl group Ethyl, methyl mercapto, methylsulfinyl, methyl sulphonyl, methysulfonylethyl, oxo, amino, amino methyl, amino are different Propyl group, methylamino, ethylamino, dimethylamino, hydroxyethylamino, hydroxypropyl, (hydroxyl) (methyl) propylcarbamic, Methoxyamino, methoxyethylamino, (hydroxyl)-(methoxyl group) (methyl) propylcarbamic, (hydroxyl) (methyl mercapto) butyl ammonia Base, N-(ethoxy)-N-(methyl) amino, Dimethylaminoethylamino, (dimethylamino) (methyl) propylcarbamic, N- (dimethyl aminoethyl)-N-(ethoxy) amino, hydroxymethyl clopentylamino, hydroxycyclobutyl methylamino, cyclopropyl, (cyclopropyl) (hydroxyl) propylcarbamic, morpholinyl ethyl-amino, oxo-pyrrolidine vlmethyl, ethylDi azoly ammonia Base, methyl thiazolium di azoly amino, benzothiazolylmethyl amino, thiazolylethyl amino, Pyrimidylmethyl amino, methylpyrazole base- Methylamino, acetyl-amino, N-acetyl group-N-methylamino, N-Isopropylcarbonyl-N-Methyl-amino, acetyl-amino first Base, ethenylcarbonylamino, double (vinyl carbonyl) amino, N-cyclopropyl carbonyl-N-methylamino, methyloxycarbonylamino, Ethoxycarbonylamino group, tertbutyloxycarbonylamino, dion e amino, ethylaminocarbonylamino, butylamino Carbonylamino, Methylsulfonylamino, N-methyl-N-(methyl sulphonyl) amino, double (methyl sulphonyl) amino, N-(carboxylic first Base)-N-methylamino, N-(carboxy ethyl)-N-methylamino, carboxyl clopentylamino, carboxycyclopropyl methylamino, formyl Base, acetyl group, Isopropylcarbonyl, cyclobutyl carbonyl, phenylcarbonyl group, acetoxyl group isopropyl, carboxyl, carboxymethyl, carboxy ethyl, Methoxycarbonyl, ethoxy carbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, Methoxycarbonylmethyl, ethoxy carbonyl first Base, ethoxycarbonylethyl group, morpholinyl ethoxy carbonyl, ethoxycarbonylmethylene, Methylsulfonylamino-carbonyl, acetyl Base amino-sulfonyl, Methoxyamino carbonyl, tetrazole radical, tetrazole radical methyl, hydroxylDi azoly, amino carbonyl, methylamino Carbonyl, hydroxyethyl aminocarbonyl, Dimethylaminocarbonyl, amino carbonyl methyl, amino-sulfonyl, methylaminosulfonyl, two Methylaminosulfonyl, methyl sulfur sulfoximide base, (methyl) (N-methyl) sulfur sulfoximide base and triazolyl.At R1、R2、R5aAnd R5b On the other example of concrete substituent group include cyanoisopropyl, cyclopropyl-sulfonyl, isopropelsulfonyl and (hydroxyl) ethyl Amino-sulfonyl.
At R1、R2、R5aAnd R5bOn the suitable example of concrete substituent group include fluorine, hydroxyl, anethane-sulfonyl, methyl, different Propyl group, methoxyl group, ethoxy carbonyl, cyclopropyl, cyclobutyl, carboxyl, methyl sulfur sulfoximide base, acetyl group, cyanoisopropyl, ring Propyl-sulfonyl, isopropelsulfonyl and (hydroxyl) ethylaminosulfonyl.
Generally, R1Represent C1-6Alkyl, C2-6Alkynyl, aryl, C3-7Heterocyclylalkyl, C3-7Heterocycloalkenyl, heteroaryl, (C3-7) Heterocyclylalkyl (C1-6) alkyl-aryl-group-, heteroaryl (C3-7) Heterocyclylalkyl-, (C3-7) cycloalkyl-heteroaryl-, (C3-7) cycloalkyl- (C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl-heteroaryl-, (C3-7) Heterocyclylalkyl-miscellaneous Aryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-heteroaryl-, (C4-9) miscellaneous bicyclic alkyl-miscellaneous Aryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl-, any one in described group can be optionally by one or more substituent groups Replace.
Suitably, R1Represent aryl, (C3-7) heterocycloalkenyl-, heteroaryl, (C3-7) Heterocyclylalkyl-heteroaryl-, (C4-9) miscellaneous Bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl, any one in described group can optionally by one or Multiple substituent groups replace.
More generally, R1Represent aryl, heteroaryl or (C3-7) Heterocyclylalkyl-heteroaryl-, arbitrary in described group Individual can optionally be substituted with one or more substituents.
In the first embodiment, R1Represent halogen.At an aspect of this embodiment, R1Represent bromine.
In second embodiment, R1Represent cyano group.
In a third embodiment, R1Represent optionally substituted C1-6Alkyl.At an aspect of this embodiment, R1 Represent optionally substituted ethyl.
In the 4th embodiment, R1Represent optionally substituted C2-6Alkynyl.At an aspect of this embodiment, R1 Represent optionally substituted butynyl.
In the 5th embodiment, R1Represent optionally substituted aryl.At an aspect of this embodiment, R1Generation The optionally substituted phenyl of table.
In the 6th embodiment, R1Represent optionally substituted C3-7Heterocyclylalkyl.
In the 7th embodiment, R1Represent optionally substituted C3-7Heterocycloalkenyl.A side in this embodiment Face, R1Represent optionally substituted 1-H-pyridin-2-ones.
In the 8th embodiment, R1Represent optionally substituted heteroaryl.At the selected aspect of this embodiment, R1 Represent benzofuranyl, thienyl, indyl, pyrazolyl, indazolyl, differentOxazolyl, thiazolyl, imidazole radicals, pyridine radicals, quinoline Quinoline base, pyridazinyl, pyrimidine radicals or pyrazinyl, any one in described group can optionally be taken by one or more substituent groups Generation.
In the 9th embodiment, R1Represent optionally substituted (C3-7)-Heterocyclylalkyl (C1-6) alkyl-aryl-group-.? The first aspect of this embodiment, R1Represent optionally substituted pyrrolidinylmethyl phenyl-.Second party in this embodiment Face, R1Represent optionally substituted piperizinylmethyl phenyl-.
In the tenth embodiment, R1Represent optionally substituted heteroaryl (C3-7)-Heterocyclylalkyl-.This embodiment party One aspect of case, R1Represent optionally substituted Pyridylpiperazine base-.
In the 11st embodiment, R1Represent optionally substituted (C3-7) cycloalkyl-heteroaryl-.This embodiment party The first aspect of case, R1Represent optionally substituted cyclohexyl pyrazolyl-.At the second aspect of this embodiment, R1Represent optionally The substituted cyclohexylmethylpyridine base in ground-.At the third aspect of this embodiment, R1Represent optionally substituted cyclopropyl-pyrimidine base-. At the fourth aspect of this embodiment, R1Represent optionally substituted cyclobutyl pyrimidines base-.The 5th side in this embodiment Face, R1Represent optionally substituted cyclopenta pyrimidine radicals-.At the 6th aspect of this embodiment, R1Represent optionally substituted ring Hexyl pyrimidine radicals-.At the 7th aspect of this embodiment, R1Represent optionally substituted cyclohexyl-pyrazinyl-.In this enforcement The eighth aspect of scheme, R1Represent optionally substituted cyclopropyl pyridine base.
In the 12nd embodiment, R1Represent optionally substituted (C4-7)-cycloalkenyl group-heteroaryl-.
In the 13rd embodiment, R1Represent optionally substituted (C3-7)-Heterocyclylalkyl-heteroaryl-.Real at this Execute the first aspect of scheme, R1Represent optionally substituted pyrollidinopyridine base-.At the second aspect of this embodiment, R1Generation Table optionally substituted THP trtrahydropyranyl pyridine radicals-.At the third aspect of this embodiment, R1Represent optionally substituted piperidines Yl pyridines base-.At the fourth aspect of this embodiment, R1Represent optionally substituted piperazinyl pyridine base-.In this embodiment The 5th aspect, R1Represent optionally substituted morpholinyl pyridine radicals-.At the 6th aspect of this embodiment, R1Represent optionally Substituted thio-morpholinyl-pyridine radicals-.At the 7th aspect of this embodiment, R1Represent optionally substituted diaza cycloheptyl Alkylpyridyl-.At the eighth aspect of this embodiment, R1Represent optionally substituted oxetanylmethoxy pyrimidine radicals-.Real at this Execute the 9th aspect of scheme, R1Represent optionally substituted azelidinyl pyrimidine radicals-.At the tenth aspect of this embodiment, R1 Represent optionally substituted tetrahydrofuran base pyrimidine radicals-.At the 11st aspect of this embodiment, R1Represent optionally substituted Pyrrolidyl pyrimidine base-.At the 12nd aspect of this embodiment, R1Represent optionally substituted THP trtrahydropyranyl-pyrimidine Base-.At the 13rd aspect of this embodiment, R1Represent optionally substituted piperidinyl pyrimidine base-.In this embodiment 14 aspects, R1Represent optionally substituted piperazinylpyrimidine base-.At the 15th aspect of this embodiment, R1Represent optionally Substituted morpholinyl pyrimidine radicals-.At the 16th aspect of this embodiment, R1Represent optionally substituted thio-morpholinyl-phonetic Piperidinyl-.At the 17th aspect of this embodiment, R1Represent optionally substituted azepan yl pyrimidines base-.In this enforcement 18th aspect of scheme, R1Represent optionally substituted oxaza heptane yl pyrimidines base-.In this embodiment the 19th Aspect, R1Represent optionally substituted Diazesuberane yl pyrimidines base-.At the 20th aspect of this embodiment, R1Represent and appoint Selection of land substituted thia Diazesuberane base-pyrimidine radicals-.At the 21st aspect of this embodiment, R1Represent optionally Substituted oxetanylmethoxy pyrazinyl-.At the 22nd aspect of this embodiment, R1Represent optionally substituted piperidyl pyrrole Piperazine base-.At the 23rd aspect of this embodiment, R1Represent optionally substituted THP trtrahydropyranyl pyridine radicals.In this enforcement 23rd aspect of scheme, R1Represent (imino group) (oxo) thiazine alkyl-pyrimidinyl group.In this embodiment the 24th Aspect, R1Represent (oxo) thiazine alkyl-pyrimidinyl group.At the 25th aspect of this embodiment, R1Represent and (dioxo) thiophene Piperazine alkyl-pyrimidinyl group.
In the 14th embodiment, R1Represent optionally substituted (C3-7)-Heterocyclylalkyl (C1-6) alkyl-heteroaryl Base-.At the first aspect of this embodiment, R1Represent optionally substituted morpholinyl methyl thienyl-.In this embodiment Second aspect, R1Represent optionally substituted morpholinyl ethyl pyrazolyl-.
In the 15th embodiment, R1Represent optionally substituted (C3-7)-heterocycloalkenyl-heteroaryl-.
In the 16th embodiment, R1Represent optionally substituted (C4-9)-miscellaneous bicyclic alkyl-heteroaryl-.At this One aspect of embodiment, R1Represent 3-azabicyclo [3.2.1] octyl pyrimidine radicals.Another side in this embodiment Face, R1Represent optionally substituted 3,7-dioxa-9-azabicyclo [3.3.1] nonyl-pyrimidine radicals.
In the 17th embodiment, R1Represent optionally substituted (C4-9)-spiroheterocyclic alkyl-heteroaryl-.Real at this Execute an aspect of scheme, R1Represent optionally substituted 2-oxa--7-aza-spiro [3,5] nonyl-pyrimidine radicals.
In the 18th embodiment, R1Represent optionally substituted (C3-7) cycloalkyl-(C1-6) alkyl-heteroaryl-. At an aspect of this embodiment, R1Represent optionally substituted cyclohexyl methyl pyrimidine radicals-.
In nineteen embodiment, R1Represent optionally substituted (C4-9)-bicyclic alkyl-heteroaryl-.
Suitably, R1Represent bromo or cyano group；Or ethyl, butynyl, phenyl, pyrrolidinyl, piperidyl, piperazinyl, Quinoline base, 1,2,3,6-tetrahydro pyridyl, benzofuranyl, thienyl, indyl, pyrazolyl, indazolyl, differentOxazolyl, thiazole Base, imidazole radicals, pyridine radicals, quinolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrrolidinylmethyl phenyl, piperizinylmethyl phenyl, Pyridylpiperazine base, cyclohexyl pyrazolyl, cyclohexylmethylpyridine base, cyclopropyl-pyrimidine base, cyclobutyl pyrimidines base, cyclopenta pyrimidine Base, cyclohexyl-pyrimidine radicals, cyclohexyl pyrazinyl, cyclohexyl methyl pyrimidine radicals, cyclohexenyl group pyridine radicals, cyclopropyl pyridine base, ring Hexenyl pyrimidine radicals, bicyclo-[3.1.0] hexyl pyridine radicals, bicyclo-[3.1.0] hexyl-pyrimidine radicals, bicyclo-[4.1.0] heptane Yl pyrimidines base, bicyclo-[2.2.2] octyl pyrimidine radicals, pyrollidinopyridine base, THP trtrahydropyranyl pyridine radicals, piperidinopyridine Base, piperazinyl-pyridine base, morpholinyl pyridine radicals, thio-morpholinyl pyridine radicals, Diazesuberane yl pyridines base, oxa-ring fourth Yl pyrimidines base, azelidinyl pyrimidine radicals, tetrahydrofuran base pyrimidine radicals, pyrrolidinyl-pyrimidine radicals, THP trtrahydropyranyl pyrimidine radicals, Piperidinyl pyrimidine base, piperazinyl-pyrimidine radicals, hexahydro-[1,2,5] thiadiazoles also [2,3-a] pyrazinyl pyrimidine radicals, morpholinyl-phonetic Piperidinyl, thio-morpholinyl pyrimidine radicals, azepan yl pyrimidines base, oxaza heptane yl pyrimidines base, Diazesuberane base Pyrimidine radicals, thia Diazesuberane yl pyrimidines base, oxetanylmethoxy pyrazinyl, piperidyl-pyrazinyl, morpholinyl methylthiophene Base, morpholinyl ethyl pyrazolyl, 3-azabicyclo [3.1.0]-hexyl pyridine radicals, 3-azabicyclo [3.1.0] hexyl are rattled away Piperazine base, 3-azabicyclo [3.1.0] hexyl-pyrimidine radicals, 2-oxa--5-azabicyclo [2.2.1] heptane yl pyrimidines base, 3-nitrogen Miscellaneous dicyclo [3.1.1] alkyl-pyrimidinyl group in heptan, 3-azabicyclo [4.1.0] Alkylpyridyl in heptan, 3-azabicyclo [4.1.0] heptan Alkyl-pyrimidinyl group, 2-oxabicyclo [2.2.2] octyl pyrimidine radicals, 3-azabicyclo [3.2.1] octyl-pyrimidine radicals, 8-nitrogen Miscellaneous dicyclo [3.2.1] octyl pyrimidine radicals, 3-oxa--8-azabicyclo [3.2.1] octyl-pyrimidine radicals, 3,6-diaza are double Ring [3.2.2] nonyl pyrimidine radicals, 3-oxa--7-azabicyclo [3.3.1]-nonyl pyrimidine radicals, 5-azaspiro [2.3] hexane Yl pyrimidines base, 5-azaspiro [2.4] alkyl-pyrimidinyl group in heptan, 2-azepine spiroheptane yl pyrimidines base, 2-oxa--6-azaspiro [3.3] alkyl-pyrimidinyl group in heptan, 2-oxa--6-azaspiro [3.4] octyl pyrimidine radicals, 2-oxa--6-azaspiro [3.5] nonane Base-pyrimidine radicals, 2-oxa--7-azaspiro [3.5] nonyl pyrimidine radicals or 2,4,8-thriazaspiro [4.5] decyl-pyrimidine radicals, (imino group) (oxo) thiazine alkyl-pyrimidinyl group, (oxo) thiazine alkyl-pyrimidinyl group and (dioxo) thiazine alkyl-pyrimidinyl group, Any one in described group can optionally be substituted with one or more substituents.It addition, R1Represent optionally by one or Multiple substituent groups substituted 1H-pyridin-2-ones.
Suitably, R1Represent phenyl, THP trtrahydropyranyl pyrimidine radicals, oxetanylmethoxy pyrimidine radicals, THP trtrahydropyranyl pyridine radicals, Pyrimidine radicals, pyrazolyl, pyridine radicals, pyrimidine radicals, morpholinyl pyrimidine radicals, piperazinyl pyridine base, Diazesuberane yl pyrimidines base, 3- Azabicyclo [3.2.1] octyl pyrimidine radicals, piperidinyl pyrimidine base, cyclobutyl pyrimidines base, (imino group) (oxo) thiazine alkyl- Pyrimidine radicals, (oxo) thiazine alkyl-pyrimidinyl group, (dioxo) thiazine alkyl-pyrimidinyl group, 2-oxa--7-azaspiro [3.5] nonane Base-pyrimidine radicals, 3,7-dioxa-9-azabicyclo [3.3.1] nonyl-pyrimidine radicals, 3-azabicyclo [3.2.1] octyl- Pyrimidine radicals or 1H-pyridin-2-ones, any one in described group can optionally be substituted with one or more substituents.
Exemplarily, R1Represent phenyl, THP trtrahydropyranyl pyrimidine radicals, oxetanylmethoxy pyrimidine radicals, Pentamethylene oxide. yl pyridines Base, pyrimidine radicals, pyrazolyl, pyridine radicals, pyrimidine radicals, morpholinyl pyrimidine radicals, piperazinyl pyridine base, Diazesuberane yl pyrimidines Base, (imino group) (oxo) thiazine alkyl-pyrimidinyl group, (oxo) thiazine alkyl-pyrimidinyl group, (dioxo) thiazine alkyl-pyrimidine Base or piperidinyl pyrimidine base, any one in described group can optionally be substituted with one or more substituents.
At R1On the exemplary of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, halo (C1-6) alkyl, cyano group, cyano group (C1-6) alkyl, nitro (C1-6) alkyl, C1-6Alkyl, (C3-7) cycloalkyl, three Methyl fluoride, trifluoroethyl, C2-6Thiazolinyl, hydroxyl, hydroxyl (C1-6) alkyl, C1-6Alkoxyl, trifluoro ethoxy, carboxyl (C3-7) cycloalkanes Epoxide, C1-6Alkylthio group, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, oxo, amino, amino-(C1-6) alkane Base, C1-6Alkyl amino, two (C1-6) alkyl amino, (C1-6) alkoxyl (C1-6) alkyl amino, N-[(C1-6) alkyl]-N-[hydroxyl (C1-6) alkyl] amino, (C2-6) alkyl-carbonyl-amino (C1-6) alkyl, C1-6Alkyl sulfonyl-amino, N-[(C1-6) alkyl]-N- [(C1-6) alkyl sulphonyl] amino, double [(C1-6) alkyl-sulfonyl base] amino, N-[(C1-6) alkyl]-N-[carboxyl (C1-6) alkane Base] amino, carboxyl (C3-7) cycloalkyl-amino, carboxyl (C3-7) cycloalkyl (C1-6) alkyl amino, formoxyl, C1-6Alkyl-carbonyl, (C2-6) alkyl-carbonyloxy base (C1-6) alkyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, morpholinyl (C1-6) alkoxy carbonyl, C2-6Alkoxy carbonyl-methylene, such as carboxylic acid electronics defined herein Isostere or prodrug moiety Ω ,-(C1-6) alkyl-Ω, amino carbonyl, amino-sulfonyl, (C1-6) alkyl sulfide sulfoximide base, [(C1-6) alkyl] [N-(C1-6) alkyl] sulfur sulfoximide base and heteroaryl.At R1On other example of optionally substituted base include (C3-7) cycloalkyl-sulfonyl and hydroxyl (C1-6) alkyl amino sulfonyl.
At R1On the suitable example of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, C-6Alkyl-carbonyl, (hydroxyl) C1-6Alkyl, (C3-7) cycloalkyl, C1-6Alkyl sulphur Acyl group, (C1-6) alkyl sulphonyl (C1-6) alkyl, (C1-6) alkyl sulfide sulfoximide base, heteroaryl, oxo, carboxyl, (cyano group) C1-6 Alkyl, (halo) C1-6Alkyl, amino-sulfonyl, (C3-7) cycloalkyl-sulfonyl and hydroxyl (C1-6) alkyl amino sulfonyl.
At R1On the suitable example of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkyl-carbonyl, (hydroxyl) C1-6Alkyl, (C3-7) cycloalkyl, C1-6Alkyl Sulfonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, (C1-6) alkyl sulfide sulfoximide base, oxo and carboxyl.
At R1On the exemplary of concrete substituent group include that one, two or three is independently selected from following replacement Base: fluorine, chlorine, methyl fluoride, fluorine isopropyl, cyano group, cyano ethyl, nitromethyla, methyl, ethyl, isopropyl, isopropyl methyl, Trifluoromethyl, trifluoroethyl, vinyl, hydroxyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, isopropoxy, three fluoro-ethoxies Base, carboxyl cyclobutoxy group, methyl mercapto, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl, oxo, amino, ammonia Ylmethyl, amino isopropyl, methylamino, dimethylamino, methoxyethylamino, N-(ethoxy)-N-(methyl) amino, Acetylaminomethyl, Methylsulfonylamino, N-methyl-N-(methyl sulphonyl) amino, double (methyl sulphonyl) amino, N- (carboxy ethyl)-N-(methyl) amino, carboxyl clopentylamino, carboxycyclopropyl methylamino, formoxyl, acetyl group, acetyl Epoxide isopropyl, carboxyl, carboxymethyl, carboxy ethyl, methoxycarbonyl, ethoxy carbonyl, n-butoxycarbonyl, tert-butoxy carbonyl Base, Methoxycarbonylmethyl, ethoxy-carbonyl methyl, ethoxycarbonylethyl group, morpholinyl ethoxy carbonyl, ethoxy carbonyl- Methylene, Methylsulfonylamino carbonyl, acetyl-amino sulfonyl, Methoxyamino-carbonyl, tetrazole radical, tetrazole radical methyl, HydroxylDi azoly, amino carbonyl, amino-sulfonyl, methyl sulfur sulfoximide base, (methyl) (N-methyl) sulfur sulfoximide base and Triazolyl.At R1On other example of concrete substituent group include cyanoisopropyl, cyclopropyl-sulfonyl, isopropelsulfonyl (hydroxyl) ethylaminosulfonyl.
At R1On the object lesson of substituent group include that one, two or three is independently selected from following substituent group: fluorine, Methyl, isopropyl, isopropyl methyl, sulfonyloxy methyl ylmethyl, hydroxyl, hydroxyisopropyl, cyclopropyl, methyl sulphonyl, carboxyl, Hydroxymethyl, acetyl group, methyl sulfur sulfoximide base, oxo, methoxyl group, amino-sulfonyl, cyanoisopropyl, cyclopropyl-sulphonyl Base, isopropelsulfonyl and (hydroxyl) ethylaminosulfonyl.
In one particular embodiment, R1By hydroxyl (C1-6) alkyl replacement.At an aspect of this embodiment, R1Quilt Hydroxyisopropyl, particularly 2-hydroxyl acrylate-2-base replace.
In second particular, R1By C1-6Alkyl sulphonyl replaces.At an aspect of this embodiment, R1 Replaced by methyl sulphonyl.
In the 3rd particular, R1It is optionally substituted by halogen.At an aspect of this embodiment, R1Replaced by fluorine.
In the 4th particular, R1By (C1-6) replacement of alkyl sulfide sulfoximide base.In this particular One aspect, R1Replaced by methyl sulfur sulfoximide base.
R1Set point value include bromine, cyano group, methoxycarbonyl-ethyl, ethoxycarbonylethyl group, hydroxyl butynyl, chlorobenzene Base, hydroxy phenyl, anethane-sulfonyl phenyl, (methyl sulphonyl) aminomethyl phenyl, aminomethyl phenyl, amino isopropyl phenyl, Acetylaminomethyl phenyl, acetylphenyl, methoxycarbonyl-phenyl, aminocarbonyl-phenyl, aminosulfonvlphenyl, acetyl Base aminosulfonvlphenyl, (methoxycarbonyl) (methyl) pyrrolidinyl, oxo-piperidine base, ethoxycarbonyl piperidin base, methyl Sulfonyl piperazinium base, morpholinyl, methyl sulphonyl-1,2,3,6-tetrahydro pyridyl, acetyl group-1,2,3,6-tetrahydro pyridyl, Tert-butoxycarbonyl-1,2,3,6-tetrahydro pyridyl, Methoxycarbonylmethyl-1,2,3,6-tetrahydro pyridyl, benzofuranyl, Thienyl, indyl, pyrazolyl, methylpyrazole base, dimethyl pyrazole oxazolyl, (methyl) [N-methyl-N-(methyl sulphonyl) ammonia Base] pyrazolyl, methylindazole base, dimethyl be differentOxazolyl, hydroxyisopropyl thiazolyl, methylimidazolyl, methylimidazole Base, pyridine radicals, THP trtrahydropyranyl pyridine radicals, fluoro-pyridine radicals, cyanopyridine-based, picolyl, (cyano group) (methyl) pyridine Base, dimethyl pyrazole piperidinyl, cyclopropyl pyridine base, trifluoromethyl pyridine base, vinylpyridine piperidinyl, hydroxyisopropyl pyridine radicals, hydroxyl Ylmethyl pyridine radicals, methoxypyridine base, (methoxyl group) (methyl) pyridine radicals, isopropoxypyrid base, trifluoro ethoxy pyridine Base, (methyl)-(trifluoro ethoxy) pyridine radicals, methylsulfonyl pyridine base, methyl sulphonyl picolyl, oxo pyridine Base, (methyl) (oxo)-pyridine radicals, (dimethyl) (oxo) pyridine radicals, aminopyridine base, dimethylaminopyridine base, dimethyl- Aminopyridine base, methoxyethylamino pyridine radicals, N-(ethoxy)-N-(methyl) amino-pyridine base, Methylsulfonylamino Pyridine radicals, [double (methyl sulphonyl) amino] pyridine radicals, carboxyl pyridine base, quinolyl, hydroxypyridazin base, pyrimidine radicals, isopropyl Pyrimidine radicals, fluorine isopropyl-pyrimidine radicals, hydroxyisopropyl pyrimidine radicals, methoxy pyrimidine base, carboxyl cyclobutoxy group-pyrimidine radicals, first sulfur Yl pyrimidines base, methyl sulphonyl pyrimidine radicals, oxo-pyrimidine base, aminopyrimidine base, Dimethylaminopyrimidine base, methoxy ethyl ammonia Yl pyrimidines base, N-(carboxy ethyl)-N-(methyl) aminopyrimidine base, carboxyl clopentylamino pyrimidine radicals, carboxycyclopropyl methyl Aminopyrimidine base, acetoxyl group isopropylpyrimidin base, ethoxycarbonylethyl group pyrimidine radicals, HYDROXYPYRAZINE base, hydroxyisopropyl pyrrole Piperazine base, pyrrolidinylmethyl phenyl, piperizinylmethyl phenyl, Pyridylpiperazine base, Carboxy-cyclohexyl pyrazolyl, carboxy cyclohex Yl pyridines base, methyl fluoride cyclopropyl-pyrimidine base, acetylaminomethyl cyclopropyl-pyrimidine base, hydroxycyclobutyl pyrimidine radicals, carboxyl- Cyclopenta pyrimidine radicals, carboxycyclohexyl pyrimidine radicals, (carboxyl) (methyl) cyclohexyl-pyrimidine radicals, (carboxyl) (hydroxyl) cyclohexyl are phonetic Piperidinyl, carboxymethyl cyclohexyl-pyrimidine radicals, ethoxy carbonyl cyclohexyl pyrimidine radicals, (methoxycarbonyl) (methyl)-cyclohexyl pyrimidine Base, (ethoxy carbonyl) (methyl) cyclohexyl pyrimidine radicals, Carboxy-cyclohexyl pyrazinyl, carboxycyclohexyl methylpyrimidine base, carboxyl Cyclohexenyl group-pyridine radicals, carboxy cyclohex alkenyl pyrimidine base, ethoxy carbonyl cyclohexenyl group pyrimidine radicals, carboxyl bicyclo-[3.1.0] are own Alkylpyridyl, carboxyl bicyclo-[3.1.0] hexyl pyrimidine radicals, ethoxy carbonyl bicyclo-[3.1.0] hexyl pyrimidine radicals, carboxyl Bicyclo-[4.1.0] alkyl-pyrimidinyl group in heptan, carboxyl bicyclo-[2.2.2] octyl pyrimidine radicals, pyrollidinopyridine base, hydroxypyrrole Alkylpyridyl, hydroxy tetrahydro pyranose pyridine radicals, piperidinopyridine base, acetylpiperidinyl pyridine radicals, (carboxyl) (methyl) Piperidinopyridine base, [(carboxyl) (methyl)-piperidyl] (fluorine) pyridine radicals, [(carboxyl) (methyl) piperidyl] (chlorine) pyridine radicals, Piperazinyl pyridine base, (methyl) (piperazinyl) pyridine radicals, cyano ethyl piperazinyl pyridine base, trifluoroethyl piperazinyl pyridine base, Methylsulfonyl piperazine yl pyridines base, anethane-sulfonyl ethyl piperazidine yl pyridines base, oxopiperazinyl pyridine radicals, acetyl group piperazine Piperazine yl pyridines base, (t-butoxycarbonylpiperazin base) (methyl) pyridine radicals, methyl piperazine yl pyridines base, carboxymethyl piperazinyl pyridine Base, carboxy ethyl piperazinyl pyridine base, ethoxy carbonyl methyl piperazinyl pyridine base, ethoxycarbonylethyl group piperazinyl pyridine Base, morpholinyl pyridine radicals, thio-morpholinyl-pyridine radicals, oxo thio-morpholinyl pyridine radicals, dioxothiomorpholinyl pyridine Base, oxo Diazesuberane base-pyridine radicals, Replacement of Oxygen by Fluorine heterocycle butyl pyrimidine base, hydroxyl oxygen heterocycle butyl pyrimidine base, hydroxyl nitrogen Heterocycle butyl-pyrimidine radicals, (hydroxyl) (methyl) azelidinyl pyrimidine radicals, carboxyl azelidinyl pyrimidine radicals, (tert-butoxy carbonyl Base) (hydroxyl) azelidinyl pyrimidine radicals, tetrazole radical azelidinyl pyrimidine radicals, hydroxyl tetrahydrofuran yl pyrimidines base, hydroxyl pyrrole Cough up alkyl base, carboxy-pyrrolidinyl pyrimidine radicals, (carboxyl) (methyl) Pyrrolidyl pyrimidine base, carboxymethyl-pyrrolidinyl phonetic Piperidinyl, ethoxy carbonyl Pyrrolidyl pyrimidine base, fluoro-THP trtrahydropyranyl pyrimidine radicals, hydroxy tetrahydro pyranose pyrimidine radicals, difluoro piperazine Piperidinyl-pyrimidine radicals, (cyano group) (methyl) piperidinyl pyrimidine base, (hydroxyl) (nitromethyla) piperidyl-pyrimidine radicals, (hydroxyl) (first Base) piperidinyl pyrimidine base, (hydroxyl) (trifluoromethyl)-piperidinyl pyrimidine base, (hydroxymethyl) (methyl) piperidinyl pyrimidine base, first Base-sulfonyl piperidinyl groups pyrimidine radicals, oxo-piperidine yl pyrimidines base, (formoxyl) (methyl)-piperidinyl pyrimidine base, carboxypiperidin base Pyrimidine radicals, (carboxyl) (fluorine) piperidyl-pyrimidine radicals, (carboxyl) (methyl) piperidinyl pyrimidine base, (carboxyl) (ethyl) piperidyl-phonetic Piperidinyl, (carboxyl) (trifluoromethyl) piperidinyl pyrimidine base, (carboxyl) (hydroxyl)-piperidinyl pyrimidine base, (carboxyl) (hydroxymethyl) Piperidinyl pyrimidine base, (carboxyl)-(methoxyl group) piperidinyl pyrimidine base, (amino) (carboxyl) piperidinyl pyrimidine base, carboxy-methyl piperazine Piperidinyl pyrimidine radicals, methoxycarbonylpiperidin yl pyrimidines base, ethoxy carbonyl-piperidinyl pyrimidine base, (ethoxy carbonyl) (fluorine) piperazine Piperidinyl pyrimidine radicals, (methoxy-carbonyl) (methyl) piperidinyl pyrimidine base, (ethyl) (methoxycarbonyl) piperidyl-pyrimidine radicals, (isopropyl) (methoxycarbonyl) piperidinyl pyrimidine base, (ethoxy carbonyl)-(methyl) piperidinyl pyrimidine base, (n-butoxy carbonyl Base) (methyl) piperidinyl pyrimidine base, (ethoxy carbonyl) (trifluoromethyl) piperidinyl pyrimidine base, (ethoxy carbonyl)-(hydroxyl first Base) piperidinyl pyrimidine base, (methoxyl group) (methoxycarbonyl) piperidyl-pyrimidine radicals, (carboxyl) (methoxycarbonyl) piperidyl be phonetic Piperidinyl, (methyl)-(morpholinyl ethoxy carbonyl) piperidinyl pyrimidine base, ethoxy carbonyl methyl piperidyl-pyrimidine radicals, methyl sulphur Acyl amino carbonyl piperazine piperidinyl pyrimidine radicals, acetyl-amino-sulfonyl piperidinyl groups pyrimidine radicals, Methoxyamino carbonyl piperazine piperidinyl are phonetic Piperidinyl, tetrazole radical piperidinyl pyrimidine base, hydroxylDi azoly piperidinyl pyrimidine base, amino-sulfonyl piperidinyl pyrimidine base, piperazine Piperazine yl pyrimidines base, methylsulfonyl piperazine base-pyrimidine radicals, oxopiperazinyl pyrimidine radicals, carboxypiperazinyl pyrimidine radicals, carboxyl second Base-piperazinylpyrimidine base, t-butoxycarbonylpiperazin yl pyrimidines base, tetrazole radical methyl-piperazinyl group pyrimidine radicals, trioxy-hexahydro- [1,2,5] thiadiazoles also [2,3-a] pyrazinyl pyrimidine radicals, morpholinyl pyrimidine radicals, dimethylated morpholinyl pyrimidine radicals, hydroxymethyl Quinoline base-pyrimidine radicals, carboxyl morpholinyl pyrimidine radicals, (carboxyl) (methyl) morpholinyl pyrimidine radicals, carboxymethyl morpholinyl pyrimidine radicals, sulfur generation Morpholinyl pyrimidine radicals, dioxo-thiomorpholinyl pyrimidine radicals, carboxyl azepan yl pyrimidines base, carboxyl oxygen azepan Base-pyrimidine radicals, oxo Diazesuberane yl pyrimidines base, (oxo Diazesuberane base) (trifluoromethyl) pyrimidine radicals, (oxo Diazesuberane base) (methoxyl group) pyrimidine radicals, (methyl) (oxo) Diazesuberane yl pyrimidines base, dioxo-thia two Azepan yl pyrimidines base, hydroxyl oxetanylmethoxy pyrazinyl, (carboxyl) (methyl) piperidyl-pyrazinyl, (ethyoxyl carbonyl Base) (methyl) piperidyl pyrazinyl, morpholinyl methyl thienyl, morpholinyl ethyl pyrazolyl, isopropyl methyl pyrazolyl, carboxylic Base-3-azabicyclo [3.1.0] hexyl pyridine radicals, carboxyl-3-azabicyclo [3.1.0] hexyl pyridazinyl, carboxyl-3-nitrogen Miscellaneous dicyclo [3.1.0] hexyl pyrimidine radicals, (carboxyl) (methyl)-3-azabicyclo [3.1.0] hexyl pyrimidine radicals, methoxyl group carbonyl Base-3-azabicyclo [3.1.0] hexyl pyrimidine radicals, ethoxy carbonyl-3-azabicyclo [3.1.0] hexyl-pyrimidine radicals, 2- Oxa--5-azabicyclo [2.2.1] heptane yl pyrimidines base, carboxyl-2-oxa--5-azabicyclo-[2.2.1] heptane yl pyrimidines Base, carboxyl-3-azabicyclo [3.1.1] heptane yl pyrimidines base, carboxyl-3-azabicyclo [4.1.0] Alkylpyridyl in heptan, carboxylic Base-3-azabicyclo [4.1.0] heptane yl pyrimidines base, methoxycarbonyl-3-azabicyclo [4.1.0] heptane yl pyrimidines base, second Epoxide carbonyl-3-azabicyclo-[4.1.0] heptane yl pyrimidines base, (hydroxyl) (methyl) (oxo)-2-oxabicyclo [2.2.2] Octyl-pyrimidine radicals, carboxyl-3-azabicyclo [3.2.1] octyl pyrimidine radicals, methoxycarbonyl-3-azabicyclo [3.2.1] Octyl pyrimidine radicals, oxo-8-azabicyclo [3.2.1] octyl pyrimidine radicals, ethoxycarbonylmethylene-8-azabicyclo [3.2.1] octyl pyrimidine radicals, 3-oxa--8-azabicyclo-[3.2.1] octyl pyrimidine radicals, oxo-3,6-diazabicyclo [3.2.2] nonyl pyrimidine radicals, carboxyl-3-oxa--7-azabicyclo [3.3.1] nonyl pyrimidine radicals, carboxyl-5-azaspiro [2.3] hexyl pyrimidine radicals, (carboxyl) (methyl)-5-azaspiro [2.3] hexyl pyrimidine radicals, carboxyl-5-azaspiro [2.4] heptan Alkyl-pyrimidinyl group, carboxyl-2-azepine spiroheptane yl pyrimidines base, 2-oxa--6-azepine spiroheptane base-pyrimidine radicals, 2-oxa--6-azaspiro [3.4] octyl pyrimidine radicals, 2-oxa--6-azaspiro [3.5] nonyl-pyrimidine radicals, 2-oxa--7- Azaspiro [3.5] nonyl pyrimidine radicals, (dioxo) (methyl)-2,4,8-thriazaspiro [4.5] decyl pyrimidine radicals, methyl sulfur Sulfoximide base phenyl, (methyl) cyclobutyl glycol-pyrimidine radicals, (imino group) (oxo) thiazine alkyl-pyrimidinyl group, (oxo) thiazine Alkyl-pyrimidinyl group and (dioxo) thiazine alkyl-pyrimidinyl group.R1Other value include that cyanoisopropyl-pyrimidine radicals, 3-azepine are double Ring [3.2.1] octyl pyrimidine radicals, 1H-pyridin-2-ones, (methyl)-1H-pyridin-2-ones, (cyclopropyl)-1H-pyridin-2-ones, (cyclopropyl) sulfonyl-phenyl, aminosulfonyl-phenyl, (isopropyl) sulfonvlphenyl and (hydroxyl) ethylaminosulfonyl- Phenyl.R1Appropriate value include bromine, fluoro-THP trtrahydropyranyl pyrimidine radicals, fluoro-oxetanylmethoxy pyrimidine radicals, Pentamethylene oxide. yl pyridines Base, isopropylpyrimidin base, isopropyl methyl pyrazolyl, methyl sulphonyl picolyl, morpholinyl pyrimidine radicals, hydroxyisopropyl Pyrimidine radicals, cyclopropyl pyridine base, (methyl) cyclobutyl glycol-pyrimidine radicals, hydroxyisopropyl pyridine radicals, carboxyl-3-azabicyclo [3.2.1] octyl, anethane-sulfonyl phenyl, hydroxy-methyl pyridine base, methylsulfonyl pyridine base, methylsulfonyl piperazine Yl pyridines base, methyl piperazine yl pyridines base, acetylpiperazinyl pyridine radicals, dimethyl pyrazole piperidinyl, methylpyrazole base, oxo phenodiazine Trioxepane yl pyrimidines base, piperazinyl pyridine base, pyridine radicals, (carboxyl) (methyl) piperidinyl pyrimidine base, methoxypyridine base, oxygen For pyridine radicals, (methyl sulphonyl) aminomethyl phenyl, methyl sulfur sulfoximide base phenyl, (imino group) (oxo) thiazine alkyl, (oxygen Generation) thiazine alkyl, (dioxo) thiazine alkyl, THP trtrahydropyranyl-pyrimidine radicals；2-oxa--7-azaspiro [3.5] nonyl pyrimidine Base, cyanoisopropyl-pyrimidine radicals, (hydroxyl) oxetanylmethoxy-pyrimidine radicals, fluorine isopropylpyrimidin base, 3,7-dioxa-9-azepine Dicyclo [3.3.1] nonyl-pyrimidine radicals, 3-azabicyclo [3.2.1] octyl pyrimidine radicals, 1H-pyridin-2-ones, (methyl)- 1H-pyridin-2-ones, (cyclopropyl)-1H-pyridin-2-ones, (cyclopropyl) sulfonyl-phenyl, (isopropyl) sulfonvlphenyl, ammonia Base sulfonyl-phenyl and (hydroxyl) ethylaminosulfonyl-phenyl.
R1Example values include bromine, fluoro-THP trtrahydropyranyl pyrimidine radicals, fluoro-oxetanylmethoxy pyrimidine radicals, THP trtrahydropyranyl Pyridine radicals, isopropylpyrimidin base, isopropyl methyl pyrazolyl, methyl sulphonyl picolyl, morpholinyl pyrimidine radicals, hydroxyl are different Propyl group pyrimidine radicals, cyclopropyl pyridine base, hydroxyisopropyl pyridine radicals, carboxyl-3-azabicyclo [3.2.1] octyl pyrimidine radicals, Anethane-sulfonyl phenyl, hydroxy-methyl pyridine base, methylsulfonyl pyridine base, methylsulfonyl piperazine yl pyridines base, methyl piperazine Piperazine yl pyridines base, acetylpiperazinyl pyridine radicals, dimethyl pyrazole piperidinyl, methylpyrazole base, oxo Diazesuberane yl pyrimidines Base, piperazinyl pyridine base, pyridine radicals, (carboxyl) (methyl) piperidinyl pyrimidine base, methoxypyridine base, oxo pyridine base and (first Base sulfonyl) aminomethyl phenyl.
At R2On the exemplary of optionally substituted base include C2-6Alkoxy carbonyl.
At R2On the exemplary of concrete substituent group include ethoxy carbonyl.
In the first embodiment, R2Represent hydrogen.
In second embodiment, R2Represent halogen.At an aspect of this embodiment, R2Represent fluorine.In this enforcement Another aspect of scheme, R2Represent chlorine.
In a third embodiment, R2Represent trifluoromethyl.
In the 4th embodiment, R2Represent optionally substituted C1-6Alkyl.At an aspect of this embodiment, R2 Represent unsubstituted methyl.At another aspect of this embodiment, R2Represent unsubstituted ethyl.In this embodiment Another aspect, R2Represent mono-substituted methyl or mono-substituted ethyl.In the 5th embodiment, R2Represent cyano group.
R2Representative value include hydrogen, fluorine, chlorine, trifluoromethyl, methyl and ethoxycarbonylethyl group.
R2Particular value include hydrogen and fluorine.
In the first embodiment, X represents oxygen atom.In second embodiment, X represents sulphur atom.
In a third embodiment, X represents-S (O).
In the 4th embodiment, X represents the straight or branched C being optionally substituted1-4Alkylidene chain.Real according to this Executing scheme, the representative value of X includes methylene (-CH2-), (methyl) methylene, ethylidene (-CH2CH2-), (ethyl) methylene, (dimethyl)-methylene, (methyl) ethylidene, propylidene (-CH2CH2CH2-), (propyl group) methylene and (dimethyl) ethylidene, Any one in described chain can optionally be substituted with one or more substituents.At an aspect of this embodiment, X represents Unsubstituted straight or branched C1-4Alkylidene chain.In the second aspect of this embodiment, X represents mono-substituted straight chain or props up Chain C1-4Alkylidene chain.In the third aspect of this embodiment, X represents dibasic straight or branched C1-4Alkylidene chain.
In a particular aspects of this embodiment, X represents unsubstituted methylene.
In the 5th embodiment, X representative-NRd.At a particular aspects of this embodiment, X representative-NH.
Carbonyl is represented the 6th embodiment X.
May reside in the example according to the Typical substituents on the alkylidene chain in the compound of the present invention include halogen, Hydroxyl, C1-6Alkoxyl, aryl ,-C (O) Rd、-CO2Rd、-CONRbRc-S(O)(N-Rd)RaOr-SO2NRbRc。
The particular value of X includes methylene ,-S (O), oxygen atom and sulphur atom.
In the first embodiment, R5aRepresent hydrogen.In second embodiment, R5aRepresentation hydroxy.The 3rd reality Execute in scheme, R5aRepresent halogen.At an aspect of this embodiment, R5aRepresent fluorine.In the 4th embodiment, R5aGeneration Table trifluoromethyl.In the 5th embodiment, R5aRepresentative-NRbRc.At an aspect of this embodiment, R5aRepresentative-NH2。 In the 6th embodiment, R5aRepresentative-NRcC(O)Rd.In the 7th embodiment, R5aRepresent-C (O)-NRcRd.? In eight embodiments, R5aRepresent-NHS (O)2Re.In the 9th embodiment, R5aRepresentative-S-Ra.The tenth embodiment party In case, R5aRepresent-S (O)-Ra.In the 11st embodiment, R5aRepresent-S (O)2Ra.A spy in this embodiment Determine aspect, R5aRepresent-S (O)2-CH3.In the 12nd embodiment, R5aRepresent-S (O) (N-Rd)Ra.The 13rd reality Execute in scheme, R5aRepresent-S (O)2(N-Rd).In the 14th embodiment, R5aRepresentative-ORa.In this embodiment one Individual aspect, RaIt is the C being optionally substituted1-6Alkyl.At the second aspect of this embodiment, RaIt it is the virtue being optionally substituted Base.At the third aspect of this embodiment, RaIt it is the heteroaryl being optionally substituted.In the 15th embodiment, R5aGeneration Table-O-(CO)-Rd.At a particular aspects of this embodiment, R5aRepresent-O-(CO)-CH3.The 16th embodiment In ,-C (O)-ORd.In the 17th embodiment, R5aRepresent optionally substituted C1-6Alkyl.In this embodiment one Individual aspect, R5aRepresent substituted C1-6Alkyl.At the second aspect of this embodiment, R5aRepresent unsubstituted C1-6Alkyl.At this One particular aspects of embodiment, R5aRepresent methyl.In the 18th embodiment, R5aRepresentative is optionally substituted C2-6Alkynyl.In nineteen embodiment, R5aRepresent the heteroaryl being optionally substituted.
In the 20th embodiment, R5aRepresent the aryl being optionally substituted.In the 21st embodiment, R5aRepresent the C being optionally substituted2-6Thiazolinyl.
In the 22nd embodiment, R5aRepresent cyano group.
R5aParticular value include hydrogen, hydroxyl, fluorine, trifluoromethyl ,-N (CH3)2、-NH(CO)CH3、-SO2-CH3、-O- (CO)-CH3, methyl, methoxyl group, (hydroxyl) ethyoxyl, (hydroxyl) propoxyl group and 2-OXo-1-pyrrolidine base-.
R5aSet point value include hydrogen, hydroxyl, fluorine, trifluoromethyl ,-N (CH3)2、-NH(CO)CH3、-SO2-CH3、-O- (CO)-CH3, methyl and methoxyl group.
In the first embodiment, R5bRepresent hydrogen.In second embodiment, R5bRepresentation hydroxy.The 3rd reality Execute in scheme, R5bRepresent halogen.At an aspect of this embodiment, R5aRepresent fluorine.In the 4th embodiment, R5bGeneration Table cyano group.In the 5th embodiment, R5bRepresent trifluoromethyl.
In the 6th embodiment, R5bRepresent optionally substituted C1-6Alkyl.At an aspect of this embodiment, R5aRepresent substituted C1-6Alkyl.At the second aspect of this embodiment, R5bRepresent unsubstituted C1-6Alkyl.This embodiment party One particular aspects of case, R5bRepresent methyl.
R5bSet point value include hydrogen and methyl.
In a certain alternative embodiments, R5aAnd R5bCarbonyl is represented together with the carbon being connected with them.
In second certain alternative embodiments, R5aAnd R5bThiocarbonyl is represented together with the carbon being connected with them.
In the 3rd certain alternative embodiments, R5aAnd R5b-C=N-OH is represented together with the carbon being connected with them.
In one particular embodiment, R5aAs defined above and R5bRepresent hydrogen.Specific of this embodiment Aspect, R5aIt it is hydroxyl.
In another particular, R5aAs defined above and R5bRepresent C1-4Alkyl, preferably methyl.Real at this Execute a particular aspects of scheme, R5aIt it is hydroxyl.
One specific subgroup of the compound of upper facial (IIB) is by the compound of formula (IIC) and its N-oxide and its medicine On, acceptable salt and solvate and its glucuronide and its eutectic represent:
Wherein
V represents C-R12Or N；
R9Represent hydrogen, halogen, halo (C1-6) alkyl, cyano group, cyano group (C1-6) alkyl, nitro (C1-6) alkyl, C1-6Alkyl, Trifluoromethyl, trifluoroethyl, C2-6Thiazolinyl, hydroxyl, hydroxyl (C1-6) alkyl, C1-6Alkoxyl, trifluoro ethoxy, carboxyl (C3-7) ring Alkoxyl, C1-6Alkylthio group, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, oxo, amino, amino-(C1-6) Alkyl, C1-6Alkyl amino, two (C1-6) alkyl amino, (C1-6) alkoxyl (C1-6) alkyl amino, N-[(C1-6) alkyl]-N-[hydroxyl Base (C1-6) alkyl] amino, (C2-6) alkyl-carbonyl-amino (C1-6) alkyl, C1-6Alkyl sulfonyl-amino, N-[(C1-6) alkyl]- N-[(C1-6) alkyl sulphonyl] amino, double [(C1-6) alkyl-sulfonyl base] amino, N-[(C1-6) alkyl]-N-[carboxyl (C1-6) alkane Base] amino, carboxyl (C3-7) cycloalkyl-amino, carboxyl (C3-7) cycloalkyl (C1-6) alkyl amino, formoxyl, C2-6Alkyl-carbonyl, (C2-6) alkyl-carbonyloxy base (C1-6) alkyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, morpholinyl (C1-6) alkoxy carbonyl, C2-6Alkoxy carbonyl-methylene, amino carbonyl, amino-sulfonyl, (C1-6) alkyl sulfide sulfoximide base, [(C1-6) alkyl] [N-(C1-6) alkyl] sulfur sulfoximide base；Or R9Represent (C3-7) cycloalkyl, (C3-7) cycloalkyl (C1-6) alkyl, (C4-7) cycloalkenyl group, (C4-9) bicyclic alkyl, (C3-7) Heterocyclylalkyl, (C3-7) heterocycloalkenyl, (C4-9) miscellaneous bicyclic alkyl, (C4-9) spiroheterocyclic alkyl or heteroaryl, any one in described group can optionally by one or Multiple substituent groups replace；Or R9Represent optionally substituted (C1-6) alkyl amino sulfonyl.
R10And R11Represent hydrogen, halogen, cyano group, trifluoromethyl, hydroxyl independently；Or-NRbRc、-ORa；Or C1-6Alkyl, C1-6Alkyl sulphonyl.
R12Represent hydrogen, halogen or C1-6Alkyl；And
X、R2、R5a、R5b、Ra、Rb、RcAs defined above.
In one embodiment, V represents C-R12.In another embodiment, V represents N.
Typically, R9Represent hydrogen, halogen, halo (C1-6) alkyl, cyano group, C1-6Alkyl, trifluoromethyl, C2-6Thiazolinyl, hydroxyl Base, hydroxyl (C1-6) alkyl, C1-6Alkoxyl, trifluoro ethoxy, carboxyl (C3-7) cycloalkyloxy, C1-6Alkylthio group, C1-6Alkyl sulfonyl Base, amino, C1-6Alkyl amino, two (C1-6) alkyl amino, (C1-6) alkoxyl (C1-6) alkyl amino, N-[(C1-6) alkyl]-N- [hydroxyl (C1-6) alkyl]-amino, N-[(C1-6) alkyl]-N-[carboxyl (C1-6) alkyl] amino, carboxyl (C3-7) cycloalkyl amino, Carboxyl (C3-7) cycloalkyl (C1-6) alkyl amino, C1-6Alkyl sulfonyl-amino, (C2-6) alkyl-carbonyl-epoxide (C1-6) alkyl, carboxylic Base, morpholinyl (C1-6) alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, C2-6Alkoxy carbonyl methylene or (C1-6) alkane Base sulfur sulfoximide base；Or R9Represent (C3-7) cycloalkyl, (C3-7) cycloalkyl-(C1-6) alkyl, (C4-7) cycloalkenyl group, (C4-9) bicyclo- Alkyl, (C3-7) Heterocyclylalkyl, (C4-9) miscellaneous bicyclic alkyl, (C4-9) spiroheterocyclic alkyl or heteroaryl, any one in described group Can optionally be substituted with one or more substituents.It addition, R9Represent cyano group (C1-6) alkyl, (C3-7) naphthene sulfamide base or (C1-6) alkyl amino sulfonyl, any one in described group can optionally be substituted with one or more substituents.Suitably Ground, R9Represent hydrogen, hydroxyl, C1-6Alkyl, (hydroxyl) C1-6Alkyl, C1-6Alkoxyl, C2-6Alkyl-carbonyl, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, (C1-6) alkyl sulfide sulfoximide base, oxo or carboxyl；Or R9Represent (C3-7) cycloalkyl, (C3-7) Heterocyclylalkyl or (C4-9) miscellaneous bicyclic alkyl；Or cyano group (C1-6) alkyl, (C3-7) naphthene sulfamide base or (C1-6) alkyl ammonia Base sulfonyl, any one in described group can optionally be substituted with one or more substituents.
Suitably, R9Represent hydrogen, hydroxyl, C1-6Alkyl, (hydroxyl) C1-6Alkyl, C1-6Alkoxyl, C2-6Alkyl-carbonyl, C1-6 Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, (C1-6) alkyl sulfide sulfoximide base, oxo or carboxyl；Or R9Represent (C3-7) cycloalkyl, (C3-7) Heterocyclylalkyl or (C4-9) miscellaneous bicyclic alkyl, any one in described group can be optionally by one Or multiple substituent group replaces.
At R9Represent (the C being optionally substituted3-7) in the case of cycloalkyl, representative value includes cyclopropyl, cyclobutyl, ring Amyl group, cyclohexyl and suberyl, any one in described group can optionally be substituted with one or more substituents.
At R9Represent (the C being optionally substituted3-7) cycloalkyl (C1-6) in the case of alkyl, representative value is cyclohexyl first Base, described group can optionally be substituted with one or more substituents.
At R9Represent (the C being optionally substituted4-7) in the case of cycloalkenyl group, representative value includes cyclobutane base, cyclopentenes Base, cyclohexenyl group and cycloheptenyl, any one in described group can optionally be substituted with one or more substituents.
At R9Represent (the C being optionally substituted4-9) in the case of bicyclic alkyl, representative value includes bicyclo-[3.1.0] hexane Base, bicyclo-[4.1.0] heptane base and bicyclo-[2.2.2] octyl, any one in described group can optionally by one or Multiple substituent groups replace.
At R9Represent (the C being optionally substituted3-7) in the case of Heterocyclylalkyl, representative value includes oxetanylmethoxy, azepine Cyclobutyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-pyranyl, piperidyl, piperazinyl, hexahydro-[1,2,5] thiadiazoles also [2, 3-a] pyrazinyl, morpholinyl, thio-morpholinyl, azepan base, oxaza heptane base, Diazesuberane base, thia Diazesuberane base, (imino group) (oxo) thiazine alkyl, (oxo) thiazine alkyl, (dioxo) thiazine alkyl, described base Any one in group can optionally be substituted with one or more substituents.
At R9Represent (the C being optionally substituted3-7) in the case of heterocycloalkenyl, representative value is optionally substituted 1,2, 3,6-tetrahydro pyridyl.
At R9Represent (the C being optionally substituted4-9) in the case of miscellaneous bicyclic alkyl, representative value includes 3-azabicyclo [3.1.0] hexyl, 2-oxa--5-azabicyclo [2.2.1] heptane base, 3-azabicyclo [3.1.1] heptane base, 3-azepine are double Ring [4.1.0] heptane base, 2-oxabicyclo [2.2.2] octyl, quininuclidinyl, 2-oxa--5-azabicyclo [2.2.2] octane Base, 3-azabicyclo [3.2.1] octyl, 8-azabicyclo-[3.2.1] octyl, 3-oxa--8-azabicyclo [3.2.1] Octyl, 3,8-diazabicyclo [3.2.1] octyl, 3,6-diazabicyclo [3.2.2] nonyl, 3-oxa--7-azepine Dicyclo [3.3.1] nonyl, 3,9-diazabicyclo-[4.2.1] nonyl, and 3,7-dioxa-9-azabicyclo [3.3.1] Nonyl, any one in described group can optionally be substituted with one or more substituents.
At R9Represent (the C being optionally substituted4-9) in the case of spiroheterocyclic alkyl, representative value includes 5-azaspiro [2.3] Hexyl, 5-azaspiro [2.4] heptane base, 2-azaspiro [3.3]-heptane base, 2-oxa--6-azepine spiroheptane base, 2- Oxa--6-azaspiro [3.4] octyl, 2-oxa--6-azaspiro-[3.5] nonyl, 2-oxa--7-azaspiro [3.5] nonane Base and 2,4,8-thriazaspiros [4.5]-decyl, any one in described group can be optionally by one or more substituent groups Replace.
At R9In the case of representing the heteroaryl being optionally substituted, representative value includes triazolyl and (methyl) triazolyl.
Exemplarily, R9Represent hydrogen, isopropyl, isopropyl methyl, hydroxyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, Carboxyl-cyclobutoxy group, methyl mercapto, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methylamino, N-[carboxy ethyl]-N-methyl- Amino, carboxyl clopentylamino, carboxycyclopropyl methylamino or ethoxycarbonvl-ethyl；Or R9Represent cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, Cyclohexyl-methyl, cyclohexenyl group, bicyclo-[3.1.0] hexyl, bicyclo-[4.1.0] heptane base, two Ring [2.2.2]-octyl, oxetanylmethoxy, azelidinyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl, Piperazinyl, hexahydro-[1,2,5] thiadiazoles also [2,3-a] pyrazinyl, morpholinyl, thio-morpholinyl, azepan base, oxygen nitrogen Trioxepane base, Diazesuberane base, thia Diazesuberane base, 3-azabicyclo [3.1.0]-hexyl, 2-oxa-- 5-azabicyclo [2.2.1] heptane base, 3-azabicyclo [3.1.1] heptane base, 3-azabicyclo-[4.1.0] heptane base, 2-oxygen Miscellaneous bicyclo-[2.2.2] octyl, 3-azabicyclo [3.2.1] octyl, 8-azabicyclo-[3.2.1] octyl, 3-oxa-- 8-azabicyclo [3.2.1] octyl, 3,6-diazabicyclo [3.2.2] nonyl, 3-oxa--7-azabicyclo [3.3.1] Nonyl, 5-azaspiro [2.3] hexyl, 5-azaspiro [2.4] heptane base or 2-azaspiro-[3.3] heptane base, described group In any one can optionally be substituted with one or more substituents.It addition, R9Represent 3,7-dioxa-9-azabicyclo [3.3.1] nonyl, cyanoisopropyl, fluorine isopropyl, methyl sulfur sulfoximide base, Cyclopropylsulfonyl, amino-sulfonyl, isopropyl Base sulfonyl or (hydroxyl) ethylaminosulfonyl.
Suitably, R9Represent hydrogen, isopropyl, isopropyl methyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, sulfonyloxy methyl Base, sulfonyloxy methyl ylmethyl；Or R9Represent cyclopropyl, oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, piperazine Base, morpholinyl, Diazesuberane base and 3-azabicyclo [3.2.1] octyl, any one in described group can be optional Be substituted with one or more substituents；Or R9Represent 3,7-dioxa-9-azabicyclo [3.3.1] nonyl, cyano group isopropyl Base, fluorine isopropyl, methyl sulfur sulfoximide base, Cyclopropylsulfonyl, amino-sulfonyl, isopropelsulfonyl or (hydroxyl) ethyl ammonia Base sulfonyl.
Suitably, R9Represent hydrogen, isopropyl, isopropyl methyl, hydroxymethyl, hydroxyisopropyl, methoxyl group, sulfonyloxy methyl Base, sulfonyloxy methyl ylmethyl；Or R9Represent cyclopropyl, oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, piperazine Base, morpholinyl, Diazesuberane base and 3-azabicyclo [3.2.1] octyl, any one in described group can be optional Be substituted with one or more substituents.
May reside in R9On the example of optionally substituted base include that one, two or three takes independently selected from following Dai Ji: halogen, halo (C1-6) alkyl, cyano group, cyano group-(C1-6) alkyl, nitro, nitro (C1-6) alkyl, C1-6Alkyl, fluoroform Base, trifluoroethyl, C2-6Thiazolinyl, hydroxyl, hydroxyl (C1-6) alkyl, C1-6Alkoxyl, difluoro-methoxy, trifluoromethoxy, three fluoro- Ethyoxyl, C1-6Alkylthio group, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, oxo, amino, C1-6Alkyl ammonia Base, two (C1-6) alkyl amino, C2-6Alkyl-carbonyl-amino, (C2-6) alkyl-carbonyl-amino-(C1-6) alkyl, C2-6Alkoxy carbonyl Amino, C1-6Alkyl sulfonyl-amino, formoxyl, C1-6Alkyl-carbonyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, Quinoline base-(C1-6) alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, C2-6Alkoxy carbonyl methylene, as fixed in the application The carboxylic acid isostere of justice or prodrug moiety Ω ,-(C1-6) alkyl-Ω, amino-carbonyl, C1-6Alkyl amino-carbonyl, two (C1-6) alkyl amino-carbonyl, amino-sulfonyl, two (C1-6) alkyl amino sulfonyl, (C1-6) alkyl sulfide sulfoximide base and [(C1-6) alkyl] [N-(C1-6) alkyl]-sulfur sulfoximide base.
At R9On the selected example of optionally substituted base include that one, two or three is independently selected from following replacement Base: halogen, C1-6Alkyl, C1-6Alkyl sulphonyl, C1-6Alkyl-carbonyl, oxo and carboxyl.
At R9On the suitable example of concrete substituent group include that one, two or three is independently selected from following replacement Base: fluorine, methyl fluoride, chlorine, bromine, cyano group, cyano methyl, cyano ethyl, nitro, nitromethyla, methyl, ethyl, isopropyl, trifluoro Methyl, trifluoroethyl, vinyl, hydroxyl, hydroxymethyl, methoxyl group, ethyoxyl, difluoro-methoxy, trifluoromethoxy, trifluoro second Epoxide, methyl mercapto, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl, oxo, amino, methylamino, diformazan Base amino, acetyl-amino, acetyl group-amino methyl, methyloxycarbonylamino, ethoxycarbonylamino group, tert-butoxycarbonyl Amino, Methylsulfonylamino, formoxyl, acetyl group, carboxyl, carboxymethyl, carboxy ethyl, methoxycarbonyl, ethoxy carbonyl, N-butoxycarbonyl, tert-butoxycarbonyl, morpholinyl-ethoxy carbonyl, Methoxycarbonylmethyl, ethoxy carbonyl methyl, second Epoxide carbonylethyl, ethoxycarbonylmethylene, acetyl-amino sulfonyl, Methoxyamino carbonyl, tetrazole radical, tetrazole radical first Base, hydroxylDi azoly, amino carbonyl, methylaminocarbonyl, dimethyl-aminocarbonyl, Methylsulfonylamino carbonyl, ammonia Base sulfonyl, methylaminosulfonyl, dimethylamino-sulfonyl, methyl sulfur sulfoximide base and (methyl) (N-methyl) sulfur sulfone are sub- Amido.
At R9On the selected example of concrete substituent group include that one, two or three is independently selected from following replacement Base: fluorine, methyl, acetyl group, oxo and carboxyl.At R9On other example of concrete substituent group include hydroxyl.
Typically, R9Represent hydrogen, fluorine, fluorine isopropyl, cyano group, methyl, isopropyl, trifluoromethyl, vinyl, hydroxyl, hydroxyl Ylmethyl, hydroxyisopropyl, methoxyl group, isopropoxy, trifluoro-ethoxy, carboxyl cyclobutoxy group, methyl mercapto, methyl sulphonyl, Sulfonyloxy methyl ylmethyl, amino, methylamino, dimethylamino, methoxyethylamino, N-(ethoxy)-N-(methyl) ammonia Base, N-[CARBOXY-ETHYL]-N-methylamino, carboxyl clopentylamino, carboxycyclopropyl methylamino, Methylsulfonylamino, Acetoxyl group isopropyl, carboxyl, ethoxycarbonylethyl group, cyclopropyl, methyl fluoride-cyclopropyl, acetylaminomethyl cyclopropyl, Hydroxycyclobutyl, carboxyl cyclopenta, carboxycyclohexyl, (carboxyl) (methyl) cyclohexyl, (carboxyl) (hydroxyl) cyclohexyl, carboxymethyl Cyclohexyl, ethoxy carbonyl cyclohexyl, (methoxycarbonyl) (methyl)-cyclohexyl, (ethoxy carbonyl) (methyl) cyclohexyl, carboxylic Butylcyclohexyl methyl, carboxyl-cyclohexenyl group, ethoxy carbonyl cyclohexenyl group, carboxyl bicyclo-[3.1.0] hexyl, ethyoxyl carbonyl Base bicyclo-[3.1.0] hexyl, carboxyl bicyclo-[4.1.0] heptane base, carboxyl bicyclo--[2.2.2] octyl, Replacement of Oxygen by Fluorine heterocycle fourth Base, hydroxyl oxetanylmethoxy, hydroxyazetidinium base, (hydroxyl) (methyl)-azelidinyl, carboxyl azelidinyl, (tertiary fourth Epoxide carbonyl) (hydroxyl) azelidinyl, tetrazole radical-azelidinyl, hydroxyl tetrahydrofuran base, pyrrolidinyl, hydroxypyrrole Alkyl, carboxy-pyrrolidinyl, (carboxyl) (methyl) pyrrolidinyl, carboxymethylpyrrolidin base, ethoxy carbonyl-pyrrolidinyl, fluorine THP trtrahydropyranyl, hydroxy tetrahydro pyranose, piperidyl, difluoro-piperidin base, (cyano group) (methyl) piperidyl, (hydroxyl) (nitro first Base) piperidyl, (hydroxyl)-(methyl) piperidyl, (hydroxyl) (trifluoromethyl) piperidyl, (hydroxymethyl) (methyl)-piperidyl, Methyl sulphonyl piperidyl, oxo-piperidine base, (formoxyl) (methyl) piperidyl, acetylpiperidinyl, carboxypiperidin base, (carboxylic Base) (fluorine) piperidyl, (carboxyl) (methyl)-piperidyl, (carboxyl) (ethyl) piperidyl, (carboxyl) (trifluoromethyl) piperidyl, (carboxyl)-(hydroxyl) piperidyl, (carboxyl) (hydroxymethyl) piperidyl, (carboxyl) (methoxyl group)-piperidyl, (amino) (carboxyl) Piperidyl, carboxymethyl piperidyl, methoxycarbonyl-piperidine base, (methoxycarbonyl) (methyl) piperidyl, (ethyl) (methoxyl group Carbonyl) piperidyl, (isopropyl) (methoxycarbonyl) piperidyl, (methoxyl group) (methoxycarbonyl) piperidyl, (carboxyl) (methoxy Base carbonyl) piperidyl, ethoxycarbonyl piperidin base, (ethoxy carbonyl)-(fluorine) piperidyl, (ethoxy carbonyl) (methyl) piperidines Base, (ethoxy carbonyl) (TRIFLUORO-METHYL) piperidyl, (ethoxy carbonyl) (hydroxymethyl) piperidyl, (n-butoxycarbonyl)- (methyl) piperidyl, (methyl) (morpholinyl ethoxy carbonyl) piperidyl, ethoxycarbonyl-methyl piperidyl, methyl sulphonyl Amino carbonyl piperidyl, acetyl-amino sulfonyl-piperidyl, Methoxyamino carbonyl piperazine piperidinyl, tetrazole radical piperidyl, hydroxylDi azoly-piperidyl, amino-sulfonyl piperidyl, piperazinyl, methyl piperazine base, cyano ethyl piperazinyl, trifluoroethyl- Piperazinyl, methylsulfonyl piperazine base, methysulfonylethyl piperazinyl, oxopiperazinyl, acetylpiperazinyl, carboxypiperazin Base, t-butoxycarbonylpiperazin base, carboxymethyl piperazinyl, carboxy ethyl piperazinyl, ethoxy carbonyl methyl piperazinyl, ethyoxyl Carbonylethyl piperazinyl, tetrazole radical methyl piperazine base, trioxy-hexahydro-[1,2,5] thiadiazoles also [2,3-a] pyrazinyl, morpholine Base, dimethylated morpholinyl, hydroxymethyl-morpholin base, carboxyl morpholinyl, (carboxyl) (methyl) morpholinyl, carboxymethyl-morpholinyl, Thio-morpholinyl, oxo thio-morpholinyl, dioxothiomorpholinyl, carboxyl-azepan base, carboxyl oxygen azepan Base, oxo Diazesuberane base, (methyl) (oxo) Diazesuberane base, dioxo-thia Diazesuberane base, carboxylic Base-3-azabicyclo [3.1.0] hexyl, (carboxyl) (methyl)-3-azabicyclo-[3.1.0] hexyl, methoxycarbonyl- 3-azabicyclo [3.1.0] hexyl, ethoxy carbonyl-3-azabicyclo [3.1.0] hexyl, 2-oxa--5-azabicyclo [2.2.1] heptane base, carboxyl-2-oxa--5-azabicyclo [2.2.1] heptane base, carboxyl-3-azabicyclo [3.1.1] heptane Base, carboxyl-3-azabicyclo-[4.1.0] heptane base, methoxycarbonyl-3-azabicyclo [4.1.0] heptane base, ethyoxyl carbonyl Base-3-azabicyclo [4.1.0] heptane base, (hydroxyl) (methyl) (oxo)-2-oxabicyclo [2.2.2] octyl, carboxyl-3- Azabicyclo [3.2.1] octyl, methoxycarbonyl-3-azabicyclo [3.2.1] octyl, oxo-8-azabicyclo [3.2.1] octyl, ethoxycarbonylmethylene-8-azabicyclo [3.2.1] octyl, 3-oxa--8-azabicyclo [3.2.1] octyl, oxo-3,6-diazabicyclo [3.2.2] nonyl, carboxyl-3-oxa--7-azabicyclo [3.3.1] Nonyl, carboxyl-5-azaspiro [2.3] hexyl, (carboxyl) (methyl)-5-azaspiro-[2.3] hexyl, carboxyl-5-azepine Spiral shell [2.4] heptane base, carboxyl-2-azepine spiroheptane base, 2-oxa--6-azepine spiroheptane base, 2-oxa--6-nitrogen Miscellaneous spiral shell [3.4] octyl, 2-oxa--6-azaspiro [3.5] nonyl, 2-oxa--7-azaspiro [3.5] nonyl, (dioxy Generation) (methyl)-2,4,8-thriazaspiro [4.5] decyl, (methyl) cyclobutyl glycol, (imino group) (oxo) thiazine alkyl, (oxo) thiazine alkyl or (dioxo) thiazine alkyl.It addition, R9Represent 3,7-dioxa-9-azabicyclo [3.3.1] nonane Base, cyanoisopropyl, fluorine isopropyl, methyl sulfur sulfoximide base, Cyclopropylsulfonyl, amino-sulfonyl, isopropelsulfonyl or (hydroxyl) ethylaminosulfonyl.
R9Appropriate value include fluorine THP trtrahydropyranyl, fluoro oxetanylmethoxy, THP trtrahydropyranyl, isopropyl, sulfonyloxy methyl Base, hydroxyisopropyl, morpholinyl, cyclopropyl, carboxyl-3-azabicyclo [3.2.1] octyl, piperazinyl, methyl piperazine base, second Acyl piperazine base, oxo Diazesuberane base, and (methyl) (carboxyl) piperidyl, hydroxyl oxetanylmethoxy, methyl sulfur sulfone are sub- Amido, 2-oxa--7-aza-spiro [3,5] nonyl, 3,7-dioxa-9-azabicyclo [3.3.1] nonyl, 3,7-dioxy Miscellaneous-9-azabicyclo [3.3.1] nonyl ,-azabicyclo [3.2.1] octyl, cyanoisopropyl, fluorine isopropyl, methyl sulfur Sulfoximide base, Cyclopropylsulfonyl, amino-sulfonyl, isopropelsulfonyl and (hydroxyl) ethylaminosulfonyl.
R9Example values include fluorine THP trtrahydropyranyl, fluoro oxetanylmethoxy, THP trtrahydropyranyl, isopropyl, methyl sulphur Acyl group, hydroxyisopropyl, morpholinyl, cyclopropyl, carboxyl-3-azabicyclo [3.2.1] octyl, piperazinyl, methyl piperazine base, Acetylpiperazinyl, oxo Diazesuberane base and (methyl) (carboxyl) piperidyl.
In one embodiment, R10Represent hydrogen.In second embodiment, R10Represent halogen.The 3rd enforcement In scheme, R10Represent cyano group.In the 4th embodiment, R10Represent trifluoromethyl.In the 5th embodiment, R10Generation Table hydroxyl.In the 6th embodiment, R10Representative-NRbRc.At an aspect of this embodiment, R10Representative-NH2.? In seven embodiments, R10Representative-ORa.At an aspect of this embodiment, R10Representation methoxy.The 8th embodiment party In case, R10Represent C1-6Alkyl.At an aspect of this embodiment, R10Represent methyl.In the 9th embodiment, R10Generation Table C1-6Alkyl sulphonyl.At an aspect of this embodiment, R10Represent methyl sulphonyl.
In one embodiment, R11Represent hydrogen.In second embodiment, R11Represent halogen.The 3rd enforcement In scheme, R11Represent cyano group.In the 4th embodiment, R11Represent trifluoromethyl.In the 5th embodiment, R11Generation Table hydroxyl.In the 6th embodiment, R11Representative-NRbRc.At an aspect of this embodiment, R11Representative-NH2.? In seven embodiments, R11Representative-ORa.At an aspect of this embodiment, R11Representation methoxy.The 8th embodiment party In case, R11Represent C1-6Alkyl.At an aspect of this embodiment, R11Represent methyl.In the 9th embodiment, R11Generation Table C1-6Alkyl sulphonyl.At an aspect of this embodiment, R11Represent methyl sulphonyl.
R10And R11Particular value include hydrogen, methyl and methyl sulphonyl independently.
Generally, R12It is hydrogen or C1-6Alkyl.
R12Particular value include hydrogen and methyl.
The specific subgroup of the compound of upper facial (IIC) by formula (IID), (IIE), (IIF), (IIG), (IIH), (IIJ), (IIK), (IIL), (IIM) and the compound of (IIN) and its N-oxide and its pharmaceutically acceptable salt and solvate, Represent with its glucuronide and its eutectic:
Wherein
T representative-CH2-or-CH2-CH2-；
U represents C (O) or S (O2)；
W represents O, S, S (O), S (O)2、S(O)(N-Rd)、N(R14) or C (R15)(R16)；
-M-representative-CH2-、-CH2CH2-or-CH2-W-CH2；
Q represents C (R15)(R16)；
R13Represent hydrogen, cyano group, halogen, halo (C1-6) alkyl, hydroxyl, C1-6Alkoxyl, C1-6Alkylthio group, C1-6Alkyl Asia sulphur Acyl group, C1-6Alkyl sulphonyl, amino, C1-6Alkyl amino, two (C1-6) alkyl-amino, (C2-6) alkyl-carbonyl-amino, (C2-6) Alkyl-carbonyl-amino (C1-6) alkyl, (C1-6) alkyl-sulfonylamino or (C1-6) alkyl sulfonyl-amino (C1-6) alkyl；
R14Represent hydrogen, cyano group (C1-6) alkyl, C1-6Alkyl, trifluoromethyl, trifluoro ethyl, C1-6Alkyl sulphonyl, (C1-6) Alkyl sulphonyl (C1-6) alkyl, formoxyl, C2-6Alkyl-carbonyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkane Epoxide carbonyl (C1-6) alkyl, carboxylic acid isostere or prodrug moiety Ω ,-(C1-6) alkyl-Ω, amino carbonyl, C1-6Alkyl ammonia Base carbonyl, two (C1-6) alkyl amino-carbonyl, amino-sulfonyl or two (C1-6) alkyl amino-sulfonyl；
R15Represent hydrogen, halogen, cyano group, hydroxyl, hydroxyl (C1-6) alkyl, C1-6Alkyl sulphonyl, formoxyl, C2-6Alkyl oxycarbonyl Base, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, amino-sulfonyl, (C1-6) alkane Base-sulfur sulfoximide base, [(C1-6) alkyl] [N-(C1-6) alkyl] sulfur sulfoximide base, carboxylic acid isostere or prodrug moiety Ω Or-(C1-6) alkyl-Ω；With
R16Represent hydrogen, halogen, C1-6Alkyl, C3-7Cycloalkyl, trifluoromethyl, hydroxyl, hydroxyl-(C1-6) alkyl, C1-6Alcoxyl Base, amino or carboxyl；
V、X、R2、R5a、R5b、R10And R11As defined above.
Generally, W represents O, S (O)2、N(R14),S(O)(N-Rd) or C (R15)(R16)。
Typically, W represents O, N (R14) or C (R15)(R16)。
In the first embodiment, W represents O.In second embodiment, W represents S.The 3rd embodiment In, W represents S (O).In the 4th embodiment, W represents S (O)2.In the 5th embodiment, W represents N (R14).? In six embodiments, W represents C (R15)(R16).In the 7th embodiment, W represents S (O) (N-Rd)。
In one embodiment ,-M-representative-CH2-.In second embodiment ,-M-representative-CH2CH2-.? In three embodiments, M represents CH2-W-CH2.At an aspect of this embodiment, M represents CH2-O-CH2.This embodiment party The second aspect of case, M represents CH2-S(O)(N-Rd)-CH2.In the third aspect of this embodiment, M represents CH2-S-CH2.At this The fourth aspect of embodiment, M represents CH2-S(O)-CH2.At the 5th aspect of this embodiment, M represents CH2-S(O)2-CH2。 At the 6th aspect of this embodiment, M represents CH2-N(R14)-CH2.At the 7th aspect of this embodiment, M represents CH2-C (R15)(R16)-CH2。
In the first embodiment, R13Represent hydrogen.
In second embodiment, R13Represent halogen.At an aspect of this embodiment, R13Represent fluorine.
In a third embodiment, R13Represent halo (C1-6) alkyl.At an aspect of this embodiment, R13Represent Methyl fluoride.
In the 4th embodiment, R13Representation hydroxy.
In the 5th embodiment, R13Represent C1-6Alkoxyl.At a particular aspects of this embodiment, R13Represent Methoxyl group.
In the 6th embodiment, R13Represent C1-6Alkylthio group.At a particular aspects of this embodiment, R13Represent Methyl mercapto.
In the 7th embodiment, R13Represent C1-6Alkyl sulphinyl.In a particular aspects of this embodiment, R13Represent methylsulfinyl.
In the 8th embodiment, R13Represent C1-6Alkyl sulphonyl.At a particular aspects of this embodiment, R13 Represent methyl sulphonyl.
In the 9th embodiment, R13Represent amino.
In the tenth embodiment, R13Represent C1-6Alkyl amino.At a particular aspects of this embodiment, R13Generation Table methylamino.
In the 11st embodiment, R13Represent two (C1-6) alkyl amino.A certain party in this embodiment Face, R13Represent dimethylamino.
In the 12nd embodiment, R13Represent (C2-6) alkyl-carbonyl-amino.A certain party in this embodiment Face, R13Represent acetyl-amino.
In the 13rd embodiment, R13Represent (C2-6) alkyl-carbonyl-amino (C1-6) alkyl.In this embodiment One particular aspects, R13Represent acetylaminomethyl.
In the 14th embodiment, R13Represent (C1-6) alkylsulfonyl-amino.A spy in this embodiment Determine aspect, R13Represent Methylsulfonylamino.
In the 15th embodiment, R13Represent (C1-6) alkyl sulfonyl-amino (C1-6) alkyl.In this embodiment A particular aspects, R13Represent Methylsulfonylamino methyl.
In the 16th embodiment, R13Represent cyano group.
Typically, R13Represent hydrogen, halogen, halo (C1-6) alkyl, hydroxyl or (C2-6) alkyl-carbonyl-amino (C1-6) alkyl.
R13Set point value include hydrogen, fluorine, methyl fluoride, hydroxyl, methoxyl group, methyl mercapto, methylsulfinyl, sulfonyloxy methyl Base, amino, methylamino, dimethylamino and acetylaminomethyl.
R13Particular value include hydrogen, fluorine, methyl fluoride, hydroxyl and acetylaminomethyl.
Suitably, R13Represent hydrogen or fluorine.
Typically, R14Represent hydrogen, cyano group (C1-6) alkyl, C1-6Alkyl, trifluoromethyl, trifluoroethyl, C1-6Alkyl sulfonyl Base, (C1-6) alkyl sulphonyl (C1-6) alkyl, formoxyl, C2-6Alkyl-carbonyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxyl carbonyl Base, C2-6Alkoxy carbonyl-(C1-6) alkyl, tetrazole radical (C1-6) alkyl, amino carbonyl, C1-6Alkyl amino-carbonyl, two (C1-6) alkane Base-amino carbonyl, amino-sulfonyl, C1-6Alkyl amino sulfonyl or two (C1-6) alkyl amino-sulfonyl.
Suitably, R14Represent hydrogen, C1-6Alkyl or C2-6Alkyl-carbonyl.
R14Representative value include hydrogen, cyano ethyl, methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, sulfonyloxy methyl Base, methysulfonylethyl, formoxyl, acetyl group, carboxyl, carboxymethyl, carboxy ethyl, methoxycarbonyl, ethoxy carbonyl, uncle Butoxy-carbonyl, ethoxy carbonyl methyl, ethoxycarbonylethyl group, tetrazole radical methyl, amino carbonyl, methylamino-carbonyl, Dimethylaminocarbonyl, amino-sulfonyl, methylaminosulfonyl and dimethylamino-sulfonyl.
R14Particular value include hydrogen, methyl and acetyl group.
In one particular embodiment, R14Represent hydrogen.
In a selected embodiment, R14Represent C1-6Alkyl.
In another particular, R14Represent C2-6Alkyl-carbonyl.
Generally, R15Represent halogen, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkane Base, carboxylic acid isostere or prodrug moiety Ω or-(C1-6) alkyl-Ω.
Typically, R15Represent hydrogen, halogen, cyano group, hydroxyl, hydroxyl (C1-6) alkyl, C1-6Alkyl sulphonyl, formoxyl, carboxylic Base, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, amino-sulfonyl, (C1-6) alkyl sulfide Sulfoximide base, [(C1-6) alkyl] [N-(C1-6) alkyl] sulfur sulfoximide base, (C1-6) alkylsulfonyl aminocarbonyl, (C2-6) alkyl Carbonylamino-sulfonyl, (C1-6) alkoxyaminocarbonyl, tetrazole radical or hydroxylDi azoly.
R15Representative value include hydrogen, fluorine, cyano group, hydroxyl, hydroxymethyl, methyl sulphonyl, formoxyl, carboxyl, carboxymethyl, Carboxy ethyl, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, Methoxycarbonylmethyl, dion e, second Epoxide carbonvlmethyl, ethoxycarbonylethyl group, amino-sulfonyl, methyl sulfur sulfoximide base, (methyl) (N-methyl) sulfur sulfoximide Base, Methylsulfonylamino carbonyl, acetyl-amino sulfonyl, Methoxyamino carbonyl, tetrazole radical and hydroxylDi azoly.
In a selected embodiment, R15Representation carboxy.
Generally, R16Represent hydrogen, halogen, C3-7Cycloalkyl or C1-6Alkyl.
Suitably, R16Represent hydrogen or C1-6Alkyl.
R16Set point value include hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, hydroxyl, hydroxymethyl, first Epoxide, amino and carboxyl.
R16Particular value include hydrogen and methyl.
In the first embodiment, R16Represent hydrogen.
In second embodiment, R16Represent halogen.At an aspect of this embodiment, R16Represent fluorine.
In a third embodiment, R16Represent C1-6Alkyl.At the first aspect of this embodiment, R16Represent methyl. At the second aspect of this embodiment, R16Represent ethyl.At the third aspect of this embodiment, R16Represent isopropyl.
In the 4th embodiment, R16Represent trifluoromethyl.
In the 5th embodiment, R16Representation hydroxy.
In the 6th embodiment, R16Representation hydroxy (C1-6) alkyl.At an aspect of this embodiment, R16Represent Hydroxymethyl.
In the 7th embodiment, R16Represent C1-6Alkoxyl.At an aspect of this embodiment, R16Represent methoxy Base.
In the 8th embodiment, R16Represent amino.
In the 9th embodiment, R16Representation carboxy.
In the tenth embodiment, R16Represent C3-7Cycloalkyl.At an aspect of this embodiment, R16Represent ring third Base.
Another specific subgroup of the compound of upper facial (IIB) by the compound of formula (IIP) and its N-oxide and its Pharmaceutically acceptable salt and solvate and its glucuronide and its eutectic represent:
X、Y、R2、R5a、R5b、R9、R10And R11As defined above.
In a particular of the compound of formula (IIP), X represents methylene.
In a particular of the compound of formula (IIP), Y represents 2-difluoro-methoxy-phenyl.In formula (IIN), in another particular of compound, Y represents the 2-chloro-phenyl of difluoro-methoxy-5-.
In a particular of the compound of formula (IIP), R2Represent hydrogen.At the compound of formula (IIP) one In individual particular, R2Represent fluorine.
In a particular of the compound of formula (IIP), R5aRepresentation hydroxy.
In a particular of the compound of formula (IIP), R5bRepresent hydrogen.
In a particular of the compound of formula (IIP), R9Represent C1-6Alkyl sulphonyl.This embodiment party One particular aspects of case, R9Represent methyl sulphonyl.In another particular of the compound of formula (IIP), R9Generation Table C3-7Naphthene sulfamide base.At a particular aspects of this embodiment, R9Represent Cyclopropylsulfonyl.Change at formula (IIP) In another particular of compound, R9Represent amino-sulfonyl.Another particular implementation at the compound of formula (IIP) In scheme, R9Represent methyl sulfur sulfoximide base.In another particular of the compound of formula (IIP), R9Represent optionally The substituted C in ground1-6Alkyl amino sulfonyl.At a particular aspects of this embodiment, R9Represent (hydroxyl) ethylamino sulphonyl Base.
In a particular of the compound of formula (IIN), R10Represent hydrogen.
In a particular of the compound of formula (IIN), R11Represent hydrogen.
Another subclass of the compound of the formula (I) according to the present invention by the compound of formula (IIQ) and its N-oxide and Its pharmaceutically acceptable salt and solvate and its glucuronide and its eutectic represent:
Wherein
Z represents hetero atom；Or-S (O) ,-S (O)2、-S(O)(N-Rd)、-NC(O)Rd、-N(CO)-ORd、-NS(O)2Rd、-N (Rd)；Or the straight or branched C being optionally substituted1-4Alkylidene chain；And
R1、R2As defined above with Y.
Typically, Z represents hetero atom；Or-NC (O) Rd、-N(CO)-ORd、-NS(O)2Rd、-N(Rd)。
Typically, RdRepresent hydrogen；Or C1-6Alkyl.
In one embodiment, RdRepresent hydrogen.In another embodiment, RdRepresent C1-6Alkyl.This embodiment party One particular aspects of case, RdRepresent methyl.
In the first embodiment, Z represents hetero atom.At an aspect of this embodiment, Z is oxygen atom.? Two aspects Z are sulfur.In second embodiment, Z represents-S (O).
In a third embodiment, Z represents-S (O)2.In the 4th embodiment, Z represents-S (O) (N-Rd).? In 5th embodiment, Z represents-NC (O) Rd.In the 6th embodiment, Z represents-N (CO)-ORd.The 7th enforcement In scheme, Z represents-NS (O)2Rd.In the 8th embodiment, Z represents-N (Rd)。
The representative value of Z includes oxygen, sulfur ,-NH ,-NCH3、-N-(SO2)-CH3、-N-(CO)-CH3With-N-(CO)-O-CH3。
One particular value of Z is sulfur.
Another subclass of the compound of the formula (I) according to the present invention by the compound of formula (IIR) and its N-oxide and Its pharmaceutically acceptable salt and solvate and its glucuronide and its eutectic represent:
Wherein
Z represents hetero atom；Or-S (O) ,-S (O)2、-S(O)(N-Rd)、-NC(O)Rd、-N(CO)-ORd、-NS(O)2Rd、-N (Rd)；Or the straight or branched C being optionally substituted1-4Alkylidene chain；And
Y、R1And R2As defined above.
Typically, Z represents hetero atom；Or-NC (O) Rd、-N(CO)-ORd、-NS(O)2Rd、-N(Rd)。
Typically, RdRepresent hydrogen, C1-6Alkyl sulphonyl or C1-6Alkyl.
In one embodiment, RdRepresent hydrogen.In second embodiment, RdRepresent C1-6Alkyl.This embodiment party One particular aspects of case, RdRepresent methyl.
In the first embodiment, Z represents hetero atom.At an aspect of this embodiment, Z is oxygen atom.? Two aspects Z are sulfur.In second embodiment, Z represents-S (O).
In a third embodiment, Z represents-S (O)2.In the 4th embodiment, Z represents-S (O) (N-Rd).? In 5th embodiment, Z represents-NC (O) Rd.In the 6th embodiment, Z represents-N (CO)-ORd.The 7th enforcement In scheme, Z represents-NS (O)2Rd.In the 8th embodiment, Z represents-N (Rd)。
The representative value of Z includes oxygen ,-NH ,-NCH3、-N-(SO2)-CH3、-N-(CO)-CH3 Hes-N-(CO)-O-CH3。
One specific subgroup of the compound of upper facial (IIR) is by the compound of formula (IIS) and its N-oxide and its medicine On, acceptable salt and solvate and its glucuronide and its eutectic represent:
Wherein
Z represents hetero atom；Or-S (O) ,-S (O)2、-S(O)(N-Rd)、-NC(O)Rd、-N(CO)-ORd、-NS(O)2Rd、-N (Rd)；Or the straight or branched C being optionally substituted1-4Alkylidene chain；And
V、Y、R2、R9、R10And R11As defined above.
Typically, Z represents hetero atom；Or-NC (O) Rd、-N(CO)-ORd、-NS(O)2Rd、-N(Rd)。
Typically, RdRepresent hydrogen, C1-6Alkyl sulphonyl or C1-6Alkyl.
In one embodiment, RdRepresent hydrogen.In second embodiment, RdRepresent C1-6Alkyl.This embodiment party One particular aspects of case, RdRepresent methyl.
In the first embodiment, Z represents hetero atom.At an aspect of this embodiment, Z is oxygen atom.? Two aspects Z are sulfur.In second embodiment, Z represents-S (O).
In a third embodiment, Z represents-S (O)2.In the 4th embodiment, Z represents-S (O) (N-Rd).? In 5th embodiment, Z represents-NC (O) Rd.In the 6th embodiment, Z represents-N (CO)-ORd.The 7th enforcement In scheme, Z represents-NS (O)2Rd.In the 8th embodiment, Z represents-N (Rd)。
The representative value of Z includes oxygen ,-NH ,-NCH3、-N-(SO2)-CH3、-N-(CO)-CH3 Hes-N-(CO)-O-CH3。
Another specific subgroup of the compound of upper facial (IIR) by the compound of formula (IIT) and its N-oxide and its Pharmaceutically acceptable salt and solvate and its glucuronide and its eutectic represent:
Wherein Z, Y, R2、R9、R10And R11As defined above.
Concrete novel compound according to the present invention is included in subsidiary embodiment and describes its every kind of change prepared Compound and its pharmaceutically acceptable salt and solvate and its eutectic.
Compound according to the present invention is useful in the treatment and/or prevention of multiple human disease.These include self Immune and struvite obstacle；Neurological and neural degeneration obstacle；Pain and nociception sexual disorders；Cardiovascular disorder；Metabolism hinders Hinder；Eye disorder；With oncology's obstacle.
Struvite and autoimmune disorders includes systemic autoimmune obstacle, autoimmunity dyshormonia and device The specific autoimmune disorders of official.Systemic autoimmune obstacle includes systemic lupus erythematosus (sle) (SLE), psoriasis, silver bits Characteristic of disease arthrosis, vasculitis, polymyositis, scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid Arthritis, nonspecific inflammatory arthritis, teenager inflammatory arthritis, Juvenile idiopathic arthritis (include that it is few Joint and multiarticulate form), the anemia (ACD) of chronic disease, Still disease (juvenile era and/or adult onset),Family name's disease and Sjogren syndrome.Autoimmunity dyshormonia includes thyroiditis.Organ specific self exempt from Epidemic disease obstacle includes Addison's disease, hemolytic or pernicious anemia, acute injury of kidney (AKI；AKI including cisplatin induction), glycosuria Sick nephropathy (DN), obstructive uropathy (including the obstructive uropathy of cisplatin induction), glomerulonephritis (include Goodpasture The glomerule of the glomerulonephritis of syndrome, immune complex mediation and Antineutrophil Cytoplasm antibody (ANCA)-relevant Nephritis), lupus nephritis (LN), slight change type nephropathy, Graves disease, idiopathic thrombocytopenic purpura, inflammatory bowel (including Crohn disease, ulcerative colitis, uncertain colitis and cryptitis), pemphigus, atopic dermatitis, self exempt from Epidemic disease hepatitis, primary biliary cirrhosis, autoimmune pulmonary inflammation, autoimmunity carditis, myasthenia gravis, spontaneity are not Educate, osteoporosis, osteopenia, aggressivity osteopathia, chondritis, cartilage degeneration and/or destruction, fibrosing disorders (include many The liver of kind of form and pulmonary fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, Heating, muscular dystrophy (including Duchenne's dystrophy) and organ-graft refection's (including renal allograft rejection).
Neurological and neural degeneration obstacle include Alzheimer, parkinson, Huntington Chorea, ischemia, apoplexy, Amyotrophic lateral sclerosis, spinal cord injury, head damage, epilepsy (seizures) and epilepsy.
Cardiovascular disorder includes thrombosis, cardiac hypertrophy, hypertension, irregular heart contraction (such as heart failure During) and sexual disorders (including erection disturbance and female sexual disorder).TNF α function regulator can be also used for controlling Treat and/or prevention myocardial infarction (seeing J.J.Wu et al., JAMA, 2013,309,2043-2044).
Dysbolismus includes diabetes (including insulin dependent diabetes mellitus (IDDM) and juvenile diabetes), dyslipidemia and generation Thank to syndrome.
Eye disorder includes that retinopathy (includes that diabetic retinopathy, proliferative retinopathy, non-proliferative regard Retinopathy and retinopathy of prematurity), macular edema (including diabetic macular edema), age relevant degeneration of macula (ARMD), vascularization (including that vascularization of cornea and new vessels are formed), retinal vein occlusion and the tunica uvea of various ways Inflammation and keratitis.
Oncology's obstacle (it can be acute or chronic) includes proliferative disorders, and particularly cancer is relevant with cancer Complication (includes bone complications, cachexia and anemia).The particular type of cancer includes that haematological malignancies (includes white blood Sick and lymphoma) and non-blood malignant tumor (include solid tumor cancer, sarcoma, meningioma, glioblastoma multiforme, Neuroblastoma, melanoma, gastric cancer and renal cell carcinoma).Chronic leukemia can be bone marrow or lymph.Leukemic kind Class includes lymphoblast property T cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic/lymphoid leukemia (CLL), hairy cell leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukaemia (AML), myelosis are different Often syndrome, chronic neutrophilic myelocytic leukemia, Acute Lymphoblastic T cell leukemia, plasmocytoma, one-tenth immunity The mast cell leukemia of cell, jacket cell leukemia, multiple myeloma, acute megakaryoblast leukemia, acute macronucleus Chronic myeloid leukemia, promyelocitic leukemia and erythroleukemia.Lymphadenomatous kind include malignant lymphoma, Hodgkin lymphoma, Non-Hodgkin lymphoma, lymphoblast property t cell lymphoma, Burkitt lymphoma, follicular lymphoma, MALT1 lymphoma and Marginal Zone Lymphoma.The kind of non-blood malignant tumor include prostate, lung, breast, rectum, colon, lymph node, bladder, Kidney, pancreas, liver, ovary, uterus, cervix uteri, brain, skin, bone, the cancer of harmonization of the stomach muscle.TNF α function regulator can also be used In increase TNF effective antitumor effect safety (see F.V.Hauwermeiren et al., J.Clin.Invest., 2013, 123,2590-2603)。
Present invention also offers a kind of pharmaceutical composition, it comprises the compound according to the present invention as above or its medicine Acceptable salt or solvate and one or more pharmaceutically acceptable carriers on.
Pharmaceutical composition according to the present invention can be taked to be suitable for be administered orally, buccal, parenteral, nose, locally, eye or rectum The form used, or it is adapted to pass through suction or the form used of insufflation.
For Orally administered, tablet that pharmaceutical composition can be taked to prepare with following material the most by conventional methods, Lozenge or the form of capsule: pharmaceutically acceptable excipient such as binding agent (the most pregelatinized corn starch, polyethylene Ketopyrrolidine or hydroxypropyl methyl cellulose)；Filler (such as lactose, microcrystalline Cellulose or calcium hydrogen phosphate)；Lubricant is (such as Magnesium stearate, Talcum or silicon dioxide)；Disintegrating agent (such as potato starch or sodium glycollate)；Or wetting agent (such as lauryl Sodium sulfate).Described tablet can be coated by method well-known in the art.Can for Orally administered flowing product To take such as solution, syrup or the form of suspension, or they can be rendered as before use with water or other is suitable The desciccate of vehicle structure.Such flowing product can be prepared with following material by conventional methods: pharmaceutically can connect The additive being subject to such as suspending agent, emulsifying agent, non-aqueous vehicles or preservative.If Shi Dang, described goods can also contain Buffer salt, correctives, coloring agent or sweeting agent.
Can suitably be formulated for Orally administered goods to provide the controlled release of reactive compound.
Using for buccal, described compositions can be to take the form of tablet or the lozenge prepared in the usual way.
The compound of formula (I) can be configured to for by injection parenteral administration, such as by bolus or defeated Note.Preparation for injection can present with unit dosage form, and such as at glass ampule or multidose container, (such as glass is tubular Bottle) in.For shapes such as suspension, solution or Emulsions that the compositions of injection can be taked such as in oiliness or aqueous vehicles Formula, or preparaton such as suspending agent, stabilizer, preservative and/or dispersant can be contained.Alternatively, described activity becomes Dividing can be in the powder type for constructing by suitable vehicle (the most aseptic pyrogen-free water) before use.
In addition to above-mentioned preparation, it is also possible to the compound of formula (I) is formulated as depot formulation.Such durative action preparation By implanting or can be used by intramuscular injection.
Nose used or is used by suction, utilizing suitable propellant, such as dichlorodifluoromethane, fluorine three chloromethane Alkane, dichlorotetra-fluoroethane, carbon dioxide or other suitable gas or admixture of gas, can be with used by compression wrap or aerosol apparatus Aerosol spray delivery form deliver the compound according to the present invention easily.
If necessary, described compositions can be presented in packaging or dispenser device, its can containing one or Multiple unit dosage forms comprising active component.Described packaging or dispenser device can be with using description.
For local application, the compound used in the present invention can be conveniently formulated to suitable ointment, and it contains There is the active component being suspended or dissolved in one or more pharmaceutically acceptable carriers.Specific support includes, such as, mineral Oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifing wax and water.Alternatively, the chemical combination used in the present invention Thing can be configured to suitable lotion, and it contains the activity being suspended or dissolved in one or more pharmaceutically acceptable carriers Component.Specific support includes, such as, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, Spermaceti stearyl alcohol, benzyl alcohol, 2-octyl dodecanol and water.
Using for eye, the compound used in the present invention can be formulated as easily in isotonic, to adjust pH nothing Micronized suspension in bacterium saline, with or without preservative such as bactericide or antifungal, such as phenylmercuric nitrate, benzene are pricked Oronain or chlorhexidine acetate.Alternatively, eye is used, compound can be formulated in ointment such as vaseline.
For rectal administration, the compound used in the present invention can be formulated as suppository easily.These can be as follows Preparation: active component being mixed with suitable non-irritating excipient, described excipient is solid in room temperature, but in rectum temperature Degree is for liquid and so will melt in the rectum to discharge active component.Such material includes, such as cocoa butter, Cera Flava and poly- Ethylene glycol.
The amount of the compound used in the present invention required for prevention or treatment particular condition is by with the compound selected Change with the disease of patient to be treated.But, it is however generally that, oral or buccal to be used, daily dose can be about In the range of 10ng/kg to 1000mg/kg, typically from 100ng/kg to 100mg/kg, such as from about 0.01mg/kg to 40mg/kg body weight；For parenteral administration, from about 10ng/kg to 50mg/kg body weight；With nose is used or by suck or Insufflation is used, from about 0.05mg to about 1000mg, such as from about 0.5mg to about 1000mg.
If necessary, according to the compound of the present invention can (such as anti-inflammatory molecular be all with another kind of forms of pharmacologically active agents Such as methotrexate or prednisolone) cooperatively use.
It will be understood by the skilled person that and there is the multiple route of synthesis that can lead to the compound according to the present invention.Under State the purpose of method and be to illustrate some in these route of synthesis, but should not be construed to by any way how Prepare the restriction of the compound according to the present invention.
Those skilled in the art it will also be appreciated that, route of synthesis can be different with the subclass of the compound of formula (I).
The compound of upper facial (IIA) can be prepared by the method comprised the following steps: made formula as shown in scheme 1 (III) intermediate and the intermediate reaction of formula (IV), obtain the compound of formula (V), wherein R1、R2、R3、R4、R5a、R5b、R6、X Defined as mentioned above for the compound of formula (IIA) with Y.
Scheme 1
Advantageously in the presence of having alkali (such as sodium hydride, potassium carbonate, cesium carbonate), carry out described reaction.At suitable solvent (such as dimethylformamide or acetonitrile) carries out described reaction in room temperature.
In the case of they are the most commercially available, by with embodiment described in those methods or people in the art The method that member's other method known is similar, can prepare the compound of formula (IV).
Such method can change with the character of some groups on the compound being present in formula (IV).
Such as:
The compound of (i) formula (IV), wherein R6It is hydrogen, can prepare with compound from formula Y-(CO)-H in several steps. Described compound can have TiCl easily4In the presence of in suitable solvent (such as dichloromethane), use C1-4Alcoxyl basic ring Propoxyl group-trimethyl silane processes.Make thus obtained intermediate and protected amine in suitable solvent (such as toluene) In pyroreaction.
(ii) alternatively, the compound of formula (IV) can be prepared as follows: is having in suitable solvent (such as ethanol) In the presence of Raney Ni (Ni Raney), the intermediate of formula (VI) is cyclized, dealkoxycarboxylatiois subsequently.
(iii) alternatively, the compound of formula (IV) can be prepared as follows: there being acid, (R is C with R-OH1-4Alkyl) exist Under make butanimide react with reducing agent (such as sodium borohydride).At suitable solvent (such as THF) in the presence of Y-Br In make thus obtained 5-alkoxyl pyrrolidin-2-one and reactive magnesium.
(iv) alternatively, the compound of formula (IV), wherein R6It is hydrogen, and X is-S, can prepare as follows: having ammonium salt Compound and the 2-sulfanyl acetic acidreaction of formula Y-(CO)-H is made in the presence of (such as ammonium carbonate).In suitable solvent (such as first Benzene) in carry out described reaction at high temperature.
As the replacement scheme of the preparation method illustrated in scheme 1, the change of formula V can be prepared according to following proposal 3 Compound: in the presence of having acid (such as sulphuric acid), in suitable solvent (such as, toluene), at high temperature, make intermediate (VII) with Intermediate (VIII) reacts, R1、R2、R3、R4、R6, X and Y as defined above, and L1It it is leaving group.One of leaving group Example is alkoxyl.
Scheme 3
In mode similar in the way of described in the preparation of the compound above for formula (V), the compound of formula (IIN) Preparation can include the intermediate preparing formula (IX), wherein R1、R2、R3、R4、R6, Y and Z be as mentioned above for the compound of formula (IIN) Defined.
Scheme 3 '
(wherein Z is-NR to the compound of formula (IIK)d, and R1、R2、R7、R8As defined above) preparation can include root Intermediate according to scheme 4 formula (XV).
Scheme 4
Typically, by making compound and the hydroxylamine reactant salt of formula (XII) in the presence of having alkali (such as triethylamine), real Existing step (i).
Step (ii) under high pressure carries out intermediate in the presence of being included in Pd/C in suitable solvent (such as, methanol) (XIII) catalytic hydrogenation.
Step (iii) is included in suitable solvent (such as dichloromethane) and makes intermediate (XIV) with protection reagent (such as Di-t-butyl carbonate) reaction, having 1 subsequently, in the presence of 1 '-carbonyl (carnonyl) diimidazole at suitable solvent (such as Dichloromethane) cyclized by treatment.
Can (wherein X be C by the compound of formula (V) in the presence of iron powder1-4Alkylidene chain or sulphur atom) change into right The compound of the formula (IIA) answered.This reaction is carried out at high temperature easily in acetic acid.
Alternatively, when X is nitrogen, can there iing P2S5In the presence of make similar conversion.
Can by the compound of formula (V), (wherein X be N-R as followsd) it is conveniently transformed into the chemical combination of formula (IIA) of correspondence Thing: tentatively reduce nitro in the presence of having acid (such as acetic acid) with iron powder, is having P subsequently2S5In the presence of in suitable solvent (example Such as, THF) in be cyclized at high temperature.
Compound (the wherein R of upper facial (IIA)5aIt is hydroxyl, and R5bHydrogen) can be by including making in formula (XVI) Between the method for precursor reactant prepare.
Advantageously, make described intermediate anti-with trimethyl silane cyanide in suitable solvent (such as dichloromethane) Should.Thus obtained intermediate can react (being similar to compound (V) above) or replaceable subsequently in acetic acid with iron powder Ground and stannyl chlorine (II), in pyroreaction, obtain the compound of desired formula (IIA).According to embodiment or this area skill The method that method known to art personnel is similar, can obtain multiple R by further for hydroxyl functionalizationaGroup.
The intermediate of formula (XVI) can obtain as follows: makes intermediate and formula NH of formula (III) as defined above2-CH (Y)-CH2-COORdCompound reaction, wherein Y and RdAs defined above.Described reaction is having alkali (such as potassium carbonate) easily In the presence of in suitable solvent (such as acetonitrile) high temperature realize.Subsequently by the compound reducing agent that obtains (such as DIBAL-H) process.
In the case of they are not available commercially, initiation material (III), (IV), (VI), (VII), (XI) and (XII) Can be by the method similar with those methods described in subsidiary embodiment or by standard side well-known in the art Prepared by method.
Below to the compound of formula (I) mention should be understood to be included in all possible subclass mentioned hereinabove and Subgroup.
By processing with suitable alkyl halide in the presence of having alkali (such as sodium hydride or silver oxide), can be by containing hydroxyl The alkylation of formula (I).By with diethylaminosulfur trifluoride (DAST) or double (2-methoxy ethyl) amino three Sulfur fluoride (BAST) processes, and the compound of the formula (I) containing hydroxyl can change into the fluoro-substituted compound of correspondence.Can The compound of the formula (I) containing hydroxyl to be changed into by two step operations two fluoro-substituted compounds of correspondence, described two steps Operation includes: (i) processes with oxidant (such as manganese dioxide)；(ii) the so obtained change containing carbonyl is processed with DAST Compound.
Can be by processing the alkylation of the formula (I) containing N-H moiety with suitable alkyl halide as follows: typical case Ground is in the temperature raised, in organic solvent (such as acetonitrile)；Or in ambient temperature, there being alkali, (such as alkali carbonate is all Such as potassium carbonate or cesium carbonate) in the presence of, at suitable solvent (such as dipolar aprotic solvent such as DMF) In.Alternatively, by having alkali (such as inorganic base such as sodium hydride, or organic base such as 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU)) in the presence of process with suitable alkyl benzenesulfonates, can be by the formula (I) containing N-H moiety Alkylation.
By using formaldehyde treated in the presence of having reducing agent (such as sodium triacetoxy borohydride), can be containing N-H The compounds methyl of the formula (I) of part.
By typically ambient temperature in the presence of having alkali (such as organic base such as triethylamine) with suitable acid chloride (such as chloroacetic chloride) or process by suitable carboxylic acid anhydride (such as acetic anhydride), can be by the chemical combination of the formula (I) containing N-H moiety Thing is acylated.
By typically having alkali (such as organic base such as triethylamine or N, N-diisopropyl ethyl-amine) in ambient temperature In the presence of with suitable C1-6Alkyl sulfonyl chloride (such as mesyl chloride) or with suitable C1-6Alkyl sulfonic acid anhydride (such as methanesulfonic acid Acid anhydride) process, the compound of the formula (I) containing N-H moiety can be changed into corresponding compound, wherein nitrogen-atoms is by C1-6Alkyl- Sulfonyl (such as methyl sulphonyl) replaces.
By with suitable C1-6Heteroaryl-alkylsulfonyl halides (such as C1-6Alkyl sulfonyl chloride such as mesyl chloride) process, can by by Amino (-NH2) compound of substituted formula (I) changes into by C1-6Alkyl sulfonyl-amino (such as Methylsulfonylamino) or Double [(C1-6) alkyl sulphonyl] the substituted corresponding compound of amino (the most double (methyl sulphonyl) amino).Similarly, by with Suitable C1-6Alkyl-sulfonyl halogen (such as C1-6Alkyl sulfonyl chloride such as mesyl chloride) process, can will be replaced by hydroxyl (-OH) The compound of formula (I) change into by C1-6The substituted corresponding compound of alkyl-sulfonyloxy (such as sulfonyloxy methyl epoxide).
By processing with 3-chlorine peroxide-benzoic acid, the compound of the formula (I) containing part-S-can be changed into containing Partly-S (O)-corresponding compound.Similarly, by with 3-chloroperoxybenzoic acid process, can by containing part-S (O)- The compound of formula (I) changes into containing part-S (O)2-corresponding compound.Alternatively, by with(peroxide Sulfate mono potassium) process, the compound of the formula (I) containing part-S-can be changed into containing part-S (O)2-corresponding chemical combination Thing.
By processing with 3-chlorine peroxide-benzoic acid, it is right to be changed into by the compound of the formula (I) containing aromatics nitrogen-atoms The N-oxide derivative answered.
By middle with suitable boron hydride (such as 3-sec-butyl lithium borohydride or boron at suitable solvent (such as THF) Sodium hydride) process, the compound of the formula (I) containing carbonyl can be changed into the alcohol of correspondence.
By with pyrrolidin-2-one orOxazolidine-2-ketone or its most substituted analog process, can be by formula (I) Bromophenyl derivative change into correspondence optionally substituted 2-oxo-pyrrolidine-1-base phenyl or 2-oxoOxazolidine-3- Base phenyl derivatives.Described reaction is having Hydro-Giene (Water Science). (I), trans-N, N '-dimethyleyelohexane in the temperature raised easily Realize in the presence of alkane-1,2-diamidogen and inorganic base (such as potassium carbonate).
By under the high pressure of CO and in high temperature butanol process, it is right the chlorphenyl derivant of formula (I) to be changed into The butyl epoxide carbonyl phenyl derivant answered.Described reaction is having dichloro [double (dicyclohexyl phosphino-) propane] Pd (II) easily Realize with in the presence of sodium carbonate.
By processing with zinc cyanide in the presence of having four-(triphenylphosphine) palladiums (0), the chlorphenyl of formula (I) can be derived Thing changes into the cyanophenyl derivatives of correspondence.Described reaction easily in suitable solvent (such as DMF) at high temperature and making Realize by microwave technology.By with the most substituted aryl or heteroaryl-boronic acids or its with organic diol (such as pinacol, 1, Ammediol or neopentyl glycol) cyclic ester that formed processes, and can be by compound (the wherein R of formula (I)1Represent halogen, such as Bromine) change into corresponding compound, wherein R1Represent the aryl or heteroaryl moieties being optionally substituted.Described reaction typically exists There are transition-metal catalyst (such as [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (II), tetrakis triphenylphosphine palladium (0) or double [3-(diphenylphosphino) ring amyl-2,4-diene-1-base] ferrum-dichloro palladium-chloride dichloromethane complex) and alkali (such as without Machine alkali such as sodium carbonate or potassium carbonate or potassium phosphate) in the presence of realize.
Can be by compound (the wherein R of formula (I) by two step operations1Represent halogen, such as bromine) change into corresponding chemical combination Thing, wherein R1Representing aryl, heteroaryl or the heterocycloalkenyl part being optionally substituted, described two step operations include: (i) is with double Valeryl two boron (bis (pinacolato) diboron) or double (neopentyl ethylene glycol) two boron (bis (neophetyl Glycolato) diboron) reaction；(ii) thus obtained compound is made and the halo-being functionalized suitably with or toluene sulphur Acyloxy-substituted aryl, heteroaryl or heterocycloalkenyl derivatives reaction.Step (i) is having transition-metal catalyst easily (such as [1,1 '-bis--(diphenylphosphino) ferrocene] palladium chloride (II) or double [3-(diphenylphosphino)-amyl-2,4-of ring bis- Alkene-1-base] ferrum-dichloro palladium-chloride dichloromethane complex) in the presence of realize.Step (ii) is having transition-metal catalyst easily (such as four-(triphenylphosphine) palladiums (0) or double [3-(diphenylphosphino) ring amyl-2,4-diene-1-base] ferrum-dichloro palladium-dichloromethane Alkane complex) and alkali (such as inorganic base such as sodium carbonate or potassium carbonate) in the presence of realize.
Can be by compound (the wherein R of formula (I) by two step operations1Represent halogen, such as bromine) change into corresponding chemical combination Thing, wherein R1Representing aryl, heteroaryl or the heterocycloalkenyl being optionally substituted, described two step operations include: (i) is suitably Solvent (such as 1,4-bis-Alkane) in, in the presence of having inorganic base (such as sodium carbonate), with corresponding optionally substituted 4,4, 5,5-tetramethyl-1,3,2-dioxaborolan alkane (dioxaborolane) derivatives reactions, and (ii) addition (three) is (sub- Benzylacetone) two palladiums (0) and tri-tert tetrafluoroborate.Described reaction realizes in applied at elevated temperature microwave technology easily.
By processing by the most substituted alkynes derivant (such as 2-hydroxyl butyl-3-alkynes), can be by the chemical combination of formula (I) Thing (wherein R1Represent halogen, such as bromine) change into corresponding compound, wherein R1Represent the C being optionally substituted2-6Alkynyl moiety. Described reaction is easily under transition-metal catalyst (such as tetrakis triphenylphosphine palladium (0)) assists, typically having iodate sub- Complete in the presence of copper (I) and alkali (such as organic base such as triethylamine).
By processing with the most substituted imdazole derivatives, typically have copper acetate (II) and organic base (such as N, N, N ', N '-tetramethylethylenediamine (TMEDA)) in the presence of, can be by compound (the wherein R of formula (I)1Represent halogen, such as bromine) Change into corresponding compound, wherein R1Represent the imidazoles-1-base section being optionally substituted.
Can be by compound (the wherein R of formula (I) by two step operations1Represent halogen, such as bromine) change into corresponding chemical combination Thing, wherein R1Representing 2-(methoxycarbonyl)-ethyl, described two step operations include: (i) reacts with acrylic acid methyl ester.；(ii) By thus obtained alkenyl derivative catalytic hydrogenation, typically via in a hydrogen atmosphere with hydrogenation catalyst (such as palladium on carbon) Process.Step (i) typically have transition-metal catalyst (such as acid chloride (II) or double (dibenzalacetone) palladium (0)) and Realize in the presence of reagent such as three (o-tolyl) phosphine.
By using diethyl in suitable solvent (such as acetonitrile) in the presence of having suitable alkali (such as potassium hydroxide) (bromine difluoro methyl) phosphonate ester processes, and the compound of the formula (I) containing hydroxy-pheny part can change into containing of correspondence The compound of the formula (I) of difluoro-methoxy-phenyl moiety.
It is said that in general, by catalytic hydrogenation the compound of formula (I) containing-C=C-functional group can be changed into containing- The corresponding compound of CH-CH-functional group, typically via in a hydrogen atmosphere, optionally having alkali (such as alkali metal hydroxide Thing such as sodium hydroxide) in the presence of with hydrogenation catalyst (such as palladium on carbon) process.
Can be as follows by compound (the wherein R of formula (I)1Represent 6-methoxypyridine-3-base) change into corresponding compound (wherein R1Represent 2-oxo-1,2-dihydro-pyrido-5-base): by processing with pyridine hydrochloride；Or by with mineral acid (such as Hydrochloric acid) heat together.By utilizing similar method, can be by compound (the wherein R of formula (I)1Represent 6-methoxyl group-4-first Yl pyridines-3-base) change into corresponding compound (wherein R1Represent 4-methyl-2-oxo-1,2-dihydropyridine-5-base)；And can With by compound (the wherein R of formula (I)1Represent 6-methoxyl group-5-picoline-3-base) change into corresponding compound (wherein R1Generation Table 3-methyl-2-oxo-1,2-dihydropyridine-5-base).
Can be by compound (the wherein R of formula (I) by catalytic hydrogenation1Represent 2-oxo-1,2-dihydropyridine-5-base) turn Corresponding compound (the wherein R of chemical conversion1Represent 2-oxo-piperidine-5-base), typically via there being hydrogenation catalyst such as platinum oxide (IV) hydrogen treat is used in the presence of.
By processing with acid (all example hydrochloric acids of such as mineral acid), can be by containing ester moiety (such as C2-6Alkoxy carbonyl is all Such as methoxycarbonyl or ethoxy carbonyl) the compound of formula (I) change into containing carboxyl (-CO2H) the corresponding chemical combination of part Thing.
By processing with acid (all example hydrochloric acids of such as mineral acid or organic acid such as trifluoroacetic acid), can be by containing N-(uncle Butoxy carbonyl) compound of formula (I) of part changes into the corresponding compound containing N-H moiety.
Alternatively, by (being selected from the alkali metal hydroxide of Lithium hydrate, sodium hydroxide and potassium hydroxide with alkali Thing；Or organic base such as Feldalat NM or Sodium ethylate) process, can be by containing ester moiety (such as C2-6Alkoxy carbonyl such as methoxy Base carbonyl or ethoxy carbonyl) the compound of formula (I) change into containing carboxyl (-CO2H) the corresponding compound of part.
By using suitably in the presence of having condensing agent (such as 1-ethyl-3-(3-Dimethyl-aminopropyl) carbodiimide) Amine process, can be containing carboxyl (-CO2H) compound of the formula (I) of part changes into the corresponding chemical combination containing amide moieties Thing.
By processing with methyl-magnesium-bromide, the compound of the formula (I) containing carbonyl (C=O) part can be changed into and contain There is-C (CH3) (OH)-part corresponding compound.Similarly, by processing with (trifluoromethyl) trimethyl silane and cesium fluoride, The compound of the formula (I) containing carbonyl (C=O) part can be changed into containing-C (CF3) (OH)-part corresponding chemical combination Thing.By processing with nitromethane, the compound of the formula (I) containing carbonyl (C=O) part can be changed into containing-C (CH2NO2) (OH)-part corresponding compound.
By processing with oxidant (such as Dess-Martin crosses iodine alkane), can be by the formula (I) containing hydroxymethyl moieties Compound changes into the corresponding compound containing formoxyl (-CHO) part.By with oxidant (such as Tetrapropyl ammonium perruthenate) Process, the compound of the formula (I) containing hydroxymethyl moieties can be changed into the corresponding compound containing carboxy moiety.
By making compound (the wherein R of formula (I)1Represent halogen, such as bromine) with suitable formula R1The compound of-H is [such as 1-(pyridin-3-yl) piperazine or morpholine] reaction, the compound of formula (I), wherein R can be prepared1Represent containing at least one nitrogen former The substituent group of son, described substituent group is connected to the remainder of described molecule via nitrogen-atoms.Described reaction is easily in transition Metallic catalyst (such as three (dibenzalacetone) two palladium (0)) auxiliary under have amination part (such as 2-dicyclohexyl phosphino-- 2 ', 4 ', 6 '-triisopropyl-xenyl (XPhos) or 2,2 '-bis-(diphenylphosphino)-1,1 '-dinaphthyls (BINAP)) and alkali (example Such as inorganic base such as sodium tert-butoxide) in the presence of realize.Alternatively, described reaction can use palladium diacetate having reagent such as [2 ', 6 '-bis-(propane-2-base epoxide) xenyl-2-base] (dicyclohexyl) phosphine and alkali (such as inorganic base such as cesium carbonate) In the presence of realize.
By processing with phosphine acyl acetic acid three ethyl in the presence of having alkali (such as sodium hydride), can be by containing oxo moieties The compound of formula (I) change into the corresponding compound containing ethoxycarbonylmethylene part.
By making compound (the wherein R of (IIC), (IIP), (IIS) or (IIT)9Represent halogen, such as chlorine) and vinyl Three Potassium borofluoride reactions, can be with compound (the wherein R of formula (IIC), (IIP), (IIS) or (IIT)9Represent vinyl). Described reaction is typically having transition-metal catalyst (such as [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (II)) Realize with in the presence of alkali (such as organic base such as triethylamine).
By with the most substituted cycloalkenyl group boric acid or its with organic diol (such as pinacol, 1,3-propylene glycol or new Pentanediol) cyclic ester that formed processes, and can be by compound (the wherein R of formula (IIC), (IIP), (IIS) or (IIT)9Represent halogen Element, such as chlorine) change into corresponding compound (wherein R9Represent the C being optionally substituted4-7Cyclo-alkenyl moieties).Described reaction allusion quotation There iing transition-metal catalyst (the most double [3-(diphenylphosphino) ring amyl-2,4-diene-1-base] ferrum-dichloro palladium-dichloro type Methane complex) and alkali (such as inorganic base such as potassium carbonate) in the presence of realize.
By optionally having alkali (such as organic base such as triethylamine or N, N-diisopropylethylamine and/or 1-methyl-2- Ketopyrrolidine, or pyridine, or inorganic base such as potassium carbonate) in the presence of make formula (IIC), (IIP), (IIS) or the compound of (IIT) (wherein R9Represent halogen, such as chlorine) with suitable formula R9Compound [such as 2-methoxyethyl amine, N-methyl-L-third ammonia of-H Acid, 2-Aminocyclopentane carboxylic acid, 3-Aminocyclopentane carboxylic acid, 1-(amino methyl) cyclopropane-carboxylic acid, azetidine-3-formic acid Methyl ester, pyrrolidine-3-alcohol, pyrrolidine-3-formic acid, piperidines-2-formic acid, piperidines-3-formic acid, 4-(1H-TETRAZOLE-5-base) piperidines, Piperazine, 1-(methyl sulphonyl) piperazine, piperazine-2-ketone, 2-(piperazine-1-base) propanoic acid, morpholine, morpholine-2-carboxylic acid, sulfur generation Quinoline, thiomorpholine 1,1-dioxide, 1,4-diazacyclo hept-5-ketone, 2-oxa--5-azabicyclo [2.2.1] heptane or suitable Local substituted azaspiro alkane] reaction, can be with compound (the wherein R of formula (IIC), (IIP), (IIS) or (IIT)9Generation Table contains the substituent group of at least one nitrogen-atoms, and described substituent group is connected to the remainder of described molecule via nitrogen-atoms).
It will be understood by the skilled person that according to the concrete scheme described the most in an embodiment, can prepare What its synthesis was not the most described in detail in detail has specific R1And R9Group or there is the compound of formula (I) of specified substituent.
From the mixture obtaining product above for any method described by the preparation according to the compound of the present invention In the case of, desired product can be separated by conventional method from it in the suitable stage, described conventional method is such as to make Standby type HPLC；Or utilize the silicon dioxide and/or the column chromatography of aluminium oxide being such as combined with suitable solvent system.
Situation at the above-mentioned mixture producing stereoisomer for preparation according to the method for the compound of the present invention Under, these isomers can be separated by routine techniques.Specifically, the specific mapping of the compound of formula (I) is obtained in expectation In the case of isomer, this can use the routine operation of fractionation enantiomer of any appropriate from corresponding enantiomer Mixture produces.Thus, such as, by making the mixture (such as racemic modification) of the enantiomer of formula (I) and suitable hands Property compound (such as chiral base) reaction, diastereoisomeric derivant (such as salt) can be obtained.May then pass through any Mode (such as by crystallization) separates diastereomer easily, and reclaims desired enantiomer, such as in diastereomeric Isomer is by with acid treatment in the case of salt.In another kind of method for splitting, use chirality HPLC can separate formula (I) Racemic modification.Additionally, if necessary, suitable chiral intermediate is used to obtain in one of said method specific right Reflect isomer.Alternatively, it is possible to obtain given enantiomer as follows: carry out enantiomer-specific enzymatic living beings Convert, such as, use the ester of esterase to hydrolyze, the then acid of the only hydrolysis of purification enantiomer-pure from unreacted ester enantiomer. In the case of expectation obtains the particular geometric isomer of the present invention, it is also possible to be used together chromatograph with intermediate or end-product Method, recrystallization and other conventional lock out operation.
In any one in above synthesis order, it may be necessary to and/or need protection on any molecule related to Sensitive group or reactive group.This can realize by means of GPF (General Protection False base, those described the most in the following documents: Protective Groups in Organic Chemistry, J.F.W.McOmie compile, Plenum Press, and 1973；And T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley& Sons, the 3rd edition, 1999.Utilize methods known in the art, can what protection group of follow-up phase removing easily in office.
Following embodiment illustrates the preparation of the compound according to the present invention.
When test in following fluorescence polarization determination, according to the compound Fluorophotometry conjugate effectively of the present invention Combination with TNF α.Additionally, effectively suppress TNF α according to some compound of the present invention in following reporter gene measures The NF-kB activation of induction.
Fluorescence polarization determination
The preparation of compound (A)
1-(2,5-dimethyl benzyl)-6-[4-(piperazine-1-ylmethyl) phenyl]-2-(pyridin-4-yl-methyl)-1H-benzene And imidazoles-hereinafter referred to as " compound (A) "-can be by WO 2013/186229 (2013 on December 19, open) Embodiment 499 described in operation or by similar operation preparation.
The preparation of fluorophore conjugate
Compound (A) (27.02mg, 0.0538mmol) is dissolved in DMSO (2mL).By 5 (-6) carboxy-fluorescein amber Amber imide (succinimyl) ester (24.16mg, 0.0510mmol) (Invitrogen catalog number (Cat.No.): C1311) is dissolved in To obtain bright yellow solution in DMSO (1mL).By two kinds of solution in mixed at room temperature, mixture becomes red.By mixture in room Temperature stirring.After mixing soon, 20 μ L aliquots are taken out and at AcOH:H2The 80:20 mixture of O dilutes and is used for LC-MS in 1200RR-6140LC-MS system analyzes.Chromatogram shows that the retention time two at 1.42 and 1.50 minutes connects The peak of near-earth eluting, the two has quality (M+H)+=860.8amu, corresponding to using 5-and 6-substituted CF 5(6)-Carboxyfluorescein group The two kinds of products formed.At another peak of 2.21 minutes of retention time, there is (M+H)+The quality of=502.8amu, it is corresponding In compound (A).For unreacted 5 (-6) CF 5(6)-Carboxyfluorescein succinimido (succinimyl) ester, do not observe Peak.The peak area of three signals is 22.0%, 39.6% and 31.4%, thus instruction is puted together to desired fluorescence at this time point 61.6% conversion ratio of two kinds of isomers of thing.Additionally, later and then took 20 μ L deciles after stirred overnight at several hours Sample, such as front dilution and carry out LC-MS analysis.The percent conversion of these time points is identified as 79.8% He 88.6%.Purified mixture in the preparation HPLC system that UV-instructs.By the fraction lyophilization of the purification merged to remove Unnecessary solvent.After lyophilization, reclaiming orange solids (23.3mg), it is equal to the fluorophore conjugate of 0.027mmol, right Should be in the total recovery of reaction with the 53% of preparation HPLC purification.
The suppression of the combination of fluorophore conjugate and TNF α
From 25 μMs start following at 10 kinds of concentration tests compound: finally measure concentration, in environment temperature with 5%DMSO Degree in 20mM Tris, 150mM NaCl, 0.05% polysorbas20 together with TNF α precincubation 60 minutes, be subsequently adding fluorescence and sew Compound, and it is further incubated for 20 hours in ambient temperature.Total at 25 μ L measures in volume, and the end of TNF α and fluorophore conjugate is dense Degree is 10nM and 10nM respectively.Plate reader (the such as Analyst HT plate reader of fluorescence polarization can detected；Or Envision plate reader) on read flat board.Use the XLfit in ActivityBaseTM(4 parameter logistic model) calculates IC50Value.
When test in fluorescence polarization determination, the compound of subsidiary embodiment is all found to show 50 μMs or more preferable IC50Value.
Reporter gene measures
The suppression of the NF-kB activation of TNF α induction
TNF α causes the activation of NF-kB pathway to the stimulation of HEK-293 cell.For determining the report cell of TNF α activity System is purchased from InvivoGen.HEK-BlueTMCD40L is to control at the IFN β minimal promoter being fused to five NF-κ B binding sites Under, stable HEK-293 transfection, the cell line of expressing SEAP (embryonic alkaline phosphatase of secretion).These cells pair The secretion of SEAP is stimulated in the way of dose dependent by TNF α, has the EC50 of 0.5ng/mL for human TNF alpha.Generalization Compound is diluted to yield 3 times of serial dilution curve (examples of 10-point from 10mM DMSO storing solution (final mensuration concentration 0.3%DMSO) As, 30,000nM to 2nM final concentration).By compound precincubation 60 minutes together with TNF α of dilution, after receiving, add 384-hole In microtitration plate and incubation 18h.Final TNF α concentration in assay plate is 0.5ng/mL.Use colorimetric measurement substrate such as QUANTI-BlueTMOr HEK-BlueTMDetection medium (InvivoGen), determines the SEAP activity in supernatant.? The suppression percentage ratio of each diluted chemical compound degree is calculated between DMSO comparison and maximum suppression (being realized by the control compound of excess), And use the XLfit in ActivityBaseTM(4 parameter logistic model) calculates IC50Value.
When test in measuring at reporter gene, some compound of subsidiary embodiment is found to show 50 μMs or more preferable IC50Value.
Embodiment
Nomenclature
Compound is named by means of ACD/Name Batch (network) 12.0 editions or Accelyrs Draw 4.0
Abbreviation
DCM: dichloromethane EtOAc: ethyl acetate
DMF:N, dinethylformamide MeOH: methanol
DMSO: dimethyl sulfoxide SiO2: silicon dioxide
Et2O: ether h: hour
THF: oxolane AcOH: acetic acid
R.t.: room temperature RT: retention time
Br.: wide M: quality
Saline: saturated sodium-chloride water solution
HPLC: high performance liquid chromatography
LCMS: liquid chromatography mass spectrography is combined
ES+: electrojet just ionizes
TEA: triethylamine
DIPEA:N, N-bis--wopropyl ethyl amine
DIAD: diisopropyl (E)-1,2-diazene dicarboxylic ester
CDI: carbonyl dimidazoles
Bs.: wide unimodal
Boc2O: Bis(tert-butoxycarbonyl)oxide
DME dimethoxy-ethane
TLC thin layer chromatography
The most saturated
Hex hexane
The most aqueous
TMSCN: trimethylsilyl cyanide
DAST: diethylaminosulfur trifluoride
By the NH by 100mL 37%w/w4OH aqueous solution mixes in 900mL MeOH, prepares the methanol solution of ammonia.
Analysis condition
All NMR are obtained at 300MHz or 400MHz.
Dry solvent and glass drying oven is used to carry out the reagent of related to air or moisture-sensitive under nitrogen atmosphere Reaction.
Make to determine all compound GCMS data using the following method:
Method 1:
ITQ 900Ion Trap Finnigan mass spectrograph is used for GC-MS analyze.This spectrometer is furnished with and is mounted with shunting/nothing Trace GC ultra (Finnigan) the type gas chromatograph of split stream inyector.Melt at the FactorFOUR deriving from Varian Separate on silicagel column (VF-5MS 15m × 0.25 33I.D., 1 μm).Use helium (purity 99.999%) as carrier gas. With without shunt mode injected sample (1 μ L), and by following for thermostat temperature sequencing: 50 DEG C keep 5min, increase to 280 DEG C (23 DEG C/min) also keep 10min.ITQ 900 spectrometer is with electron collision (EI) or chemi-ionization (Cl-CH4) mode operation. Source temperature is set in 150 DEG C.
Make to determine all compound L CMS data using the following method.
Method 2:
Waters Acquity-SQD, Waters Acquity UPLC BEH C18,2.1 × 50mm, 1.7 μm posts
Mobile phase A: 10mM ammonium formate+0.1% ammonia
Mobile phase B: 95%MeCN+5%H2O+0.1% ammonia
Gradient program (flow velocity 1.0mL/min, column temperature 40 DEG C):
Method 1b:
Waters Acquity-SDS, Waters Acquity BEH C18,2.1 × 50mm, 1.7 μm posts
Mobile phase A: water+0.5% formic acid
Mobile phase B: MeCN+0.035% formic acid
Gradient program (flow velocity 0.9mL/min, column temperature 55 DEG C):
Preparation HPLC
Method 2b:
Post: MerckSTAR-RP18；25mm × 250mm, 10 μ are in ambient temperature
Eluent: MeCN:H2O+0.05%TFA (flow velocity 25ml/min)
Gradient: 5:95 (0min)-> 95:5 (45min),
Method 2d:
Post: Agilent Prep C-18,30mm × 250mm, 10 μ are in ambient temperature
Eluent: MeCN:H2O (flow velocity 75ml/min)
Gradient: 10:90 (0min)-> 90:10 (12.5min)-> 90:10 (15min)
It will be understood by the skilled person that if using different analysis conditions, GCMS and LCMS data can be obtained Different retention times (RT).
Intermediate 1
4-(2,5-3,5-dimethylphenyl)-4-hydroxy-butyric acid ethyl ester
Add in the 2,5-dimethylbenzaldehyde (5.00g, 37.27mmol) solution in DCM (75mL) at-78 DEG C TiCl4(41.0mL, 40.99mmol, the 1M solution in DCM).Add (1-ethoxy basic ring propoxyl group)-trimethyl-silane (7.79g, 44.72mmol) solution in DCM (30mL), and reactant at-78 DEG C of stirring 30min and is warmed to room temperature guarantor Hold 18h.Reactant is used saturated NH4Cl aqueous solution (100mL) processes, and extracts with DCM (100mL).Organic layer is separated, does Dry (MgSO4) and concentrate in a vacuum, obtain title compound (8.25g, 94%).1H NMR(400MHz,CDCl3)δ7.31 (m,1H),7.06(m,2H),5.26(m,1H),4.15(m,3H),2.57(m,2H),2.39(m,8H),1.28(m,3H)。GC- MS m/z 218.1(M-18)。
Intermediate 2
5-(2,5-3,5-dimethylphenyl)-1-[(4-methoxyphenyl) methyl] pyrrolidin-2-one
(4-methoxyphenyl) methylamine is added in the intermediate 1 (2.00g, 8.46mmol) solution in toluene (35mL) (11.61g, 84.6mmol), and reactant is heated in sealed tube 150 DEG C of holding 4h.Reactant is cooled down and uses water (50mL) process with DCM (50mL), organic layer is separated, is dried (MgSO4) and concentrate in a vacuum.Pass through column chromatography (SiO2, the ammonia of 0-3% solution/DCM in methanol) and purification residue, obtain title compound (1.20g, 40%).1H NMR (400MHz,CDCl3)δ7.04(m,4H),6.92(s,1H),6.82(d,J 8.6Hz,2H),5.12(m,1H),4.62(m, 1H),3.79(m,3H),3.48(m,1H),2.62(m,1H),2.49(m,1H),2.37(m,5H),2.10(m,3H)。LCMS(ES+)310.3(M+H)+。
Intermediate 3
5-(2,5-3,5-dimethylphenyl) pyrrolidin-2-one
By intermediate 2 (1.00g, 3.23mmol) and molecular sieve (1.5g) it is suspended in TFA (4mL) and methoxybenzene (2mL) in solution.Reactant mixture is heated 18h at 110 DEG C in sealed tube.Reactant mixture is cooled down, and uses DCM (20mL) extraction, washs with water (20mL), saline (20mL), and is separated by organic layer, is dried (MgSO4) and the denseest Contracting.By column chromatography (SiO2, the ammonia of 0-3% solution/DCM in methanol) and purification residue, obtain title compound (0.12g, 20%).1H NMR(400MHz,CDCl3)δ7.28(m,1H),7.19(m,1H),7.11(m,1H),6.55(m,1H), 5.04(m,1H),2.75(m,1H),2.57(m,2H),2.46(s,3H),2.43(s,3H),1.99(m,1H)。LCMS(ES+) 190.2(M+H)+。
Intermediate 4 (method A)
1-(5-bromo-2-nitro-phenyl)-5-(2,5-3,5-dimethylphenyl) pyrrolidin-2-one
In the intermediate 3 (0.14g, 0.74mmol) solution in dry DMF (6mL), addition sodium hydride (0.04g, 0.89mmol), and by reactant mixture 10min is stirred at room temperature.Be subsequently adding the 2-bromo-Nitrobenzol of fluoro-4-(0.18g, 0.81mmol) the solution in DMF (2mL), and reactant is stirred at room temperature 18h.By dilute for reactant mixture DCM (20mL) Release, wash with water (20mL), saline (20mL), and organic layer is separated, is dried (MgSO4) and concentrate in a vacuum.By remnants Thing and Et2O grinds together, obtains title compound (0.11g, 38%).1H NMR(400MHz,CDCl3)δ7.80(m,1H), 7.46(m,1H),7.33(m,1H),7.06(m,4H),5.47(m,1H),2.72(m,3H),2.35(m,3H),2.28(m,3H)。 LCMS(ES+)389.2/391.2(M+H)+。
Intermediate 5
The bromo-1-of 2-[2-(difluoro-methoxy) phenyl] ethyl ketone
Dropwise add in 2 '-(difluoro-methoxy) acetophenones (2.00g, 10.74mmol) solution in MeOH (40mL) Enter the bromine (1.72g, 10.74mmol) solution in MeOH (5mL).Mixture is stirred 30min at 70 DEG C.By reactant very Aerial concentration, and residue with water (10mL) is washed, and extract with DCM (20mL), be dried (MgSO4) and the denseest Contracting, obtains title compound (2.58g, 88%).1H NMR(400MHz,CDCl3)δ7.86(m,1H),7.62(m,1H),7.38 (m,1H),7.21(m,1H),6.67(m,1H),4.54(m,2H)。GC-MS m/z265.0/267.0(M+H)+。
Intermediate 6
2-[2-[2-(difluoro-methoxy) phenyl]-2-oxo-ethyl] propane diethyl adipate
In the intermediate 5 (2.50g, 9.41mmol) solution in anhydrous THF (50mL) add sodium hydride (0.56g, 14.12mmol), reactant mixture is stirred 1h at 0 DEG C, and is added dropwise over diethyl malonate (1.81g, 11.3mmol) and exists Solution in THF (5mL).Reactant is stirred at room temperature 18h.Reactant mixture EtOAc (20mL) is diluted, and uses water (20mL) wash with saline (20mL).Organic layer is separated, is dried (MgSO4) and concentrate in a vacuum, obtain title compound (1.52g, 46%).1H NMR(400MHz,DMSO-d6)δ7.77(dd,J 7.8Hz,J 1.7Hz,1H),7.68(m,1H), 7.35(m,3H),4.14(m,6H),3.93(t,J 7.1Hz,1H),3.54(d,J 7.1Hz,2H),1.19(m,4H)。LCMS (ES+)345.2(M+H)+。
Intermediate 7
2-[2-[2-(difluoro-methoxy) phenyl]-2-oximido-ethyl] propane diethyl adipate
In the intermediate 6 (1.30g, 3.78mmol) solution in pyridine (10mL) add oxammonium hydrochloride. (0.52g, 7.55mmol), at 60 DEG C of stirring 20h and being concentrated in a vacuum by reactant mixture, (2.00g quantitatively receives to obtain title compound Rate).LCMS(ES+)360.3(M+H)+。
Intermediate 8
5-[2-(difluoro-methoxy) phenyl]-2-oxo-pyrroli-3-Ethyl formate
In the intermediate 7 (2.00g, 3.78mmol) solution in EtOH (50mL), add Raney Ni (10%mol). Autoclave is sealed and heats 18h at 60 DEG C under the hydrogen of 10 bars.Reactant is filtered through kieselguhr, and uses EtOH (20mL) washing.Concentrated filtrate in a vacuum.By column chromatography (SiO2, the ammonia of 0-3% solution/DCM in methanol) and pure Change residue, obtain title compound (0.36g, 32%).1H NMR(400MHz,CDCl3)δ7.06(m,4H),6.34(m, 1H),4.92(m,1H),3.92(m,2H),3.18(m,1H),2.68(m,1H),2.06(m,1H),1.39(m,1H),1.02(m, 3H)。LCMS(ES+)300.2(M+H)+。
Intermediate 9
5-[2-(difluoro-methoxy) phenyl] pyrrolidin-2-one
In the intermediate 8 (4.0g, 13.0mmol) solution in EtOH (150mL), addition 1N sodium hydroxide (15mL, 15mmol).Mixture is stirred at room temperature 18h.Reactant mixture use water (20mL) is diluted, and washs with DCM (50mL).Will Organic layer is abandoned, and is processed by aqueous layer 1N HCl (15mL, 15mmol), and extracts with DCM (50mL).Organic layer is divided From, be dried (MgSO4) and concentrate in a vacuum.Residue is dissolved in toluene (50mL), and by mixture 110 DEG C of stirrings 18h.Reactant use water (20mL) is diluted, and extracts with DCM (50mL)；Organic layer is separated, is dried (MgSO4) and in vacuum Middle concentration.By column chromatography (SiO2, the ammonia of 0-3% solution/DCM in methanol) and purification residue, obtain title compound Thing (0.64g, 21%).1H NMR(400MHz,CDCl3)δ7.44(m,1H),7.35(m,1H),7.24(m,1H),7.14(m, 1H),6.59(m,1H),6.18(m,1H),5.15(m,1H),2.67(m,1H),2.46(m,2H),1.97(m,1H)。LCMS(ES+)228.1(M+H)+。
Intermediate 10
1-(5-bromo-2-nitro-phenyl)-5-[2-(difluoro-methoxy) phenyl] pyrrolidin-2-one
By method A, from intermediate 9 (0.13g, 0.57mmol) and the bromo-Nitrobenzol of the fluoro-4-of 2-(0.14g, 0.63mmol) Prepare title compound (0.09g, 37%).1H NMR(400MHz,CDCl3)δ7.81(m,1H),7.65(m,1H),7.41(m, 1H),7.31(m,1H),7.22(m,2H),7.14(m,1H),6.64(m,1H),5.74(m,1H),2.71(m,3H),2.16(m, 1H)。LCMS(ES+)427.2/429.2(M+H)+。
Intermediate 11 and 12
Enantiomer 1 (5S or R)-5-[2-(difluoro-methoxy) phenyl] pyrrolidin-2-oneWithEnantiomer 2 (5R Or S)-5-[2-(difluoro-methoxy) phenyl] pyrrolidin-2-one
By under the conditions of SFC Chiralpak IA (50*226,360mL/min, 25 DEG C, CO2+ 10%MeOH is dense Degree: 20g/l) upper purification, separates following title compound from intermediate 9 (0.47g), respectively obtains intermediate 11 (RT 3.9min, 0.20g) and intermediate 12 (RT 5.4min, 0.22g).
Intermediate 13
Enantiomer 1 (5S or R)-1-(5-bromo-2-nitro-phenyl)-5-[2-(difluoro-methoxy) phenyl] pyrrolidine- 2-ketone
By method A, (0.40g determines to prepare title compound from intermediate 11 (0.20g) and the bromo-Nitrobenzol of the fluoro-4-of 2- Amount yield).LCMS(ES+)427.2/429.2(M+H)+。
Intermediate 14
Enantiomer 2 (5R or S)-1-(5-bromo-2-nitro-phenyl)-5-[2-(difluoro-methoxy) phenyl] pyrrolidine- 2-ketone
By method A, from intermediate 12 (0.22g) and the bromo-Nitrobenzol of the fluoro-4-of 2-prepare title compound (0.40g, 91%).LCMS(ES+)427.2/429.2(M+H)+。
Intermediate 15
4-hydroxyl-4-(o-tolyl) ethyl n-butyrate.
In the 2-tolyl aldehyde (3.0g, 25.0mmol) solution in DCM (60mL), TiCl is added at-78 DEG C4 (40.0mL, 40mmol, the 1M solution in DCM).Addition (1-ethoxy basic ring propoxyl group)-trimethyl-silane (8.70g, 50.0mmol) the solution in DCM (20mL), and reactant at-78 DEG C of stirring 30min and is warmed to room temperature holding 18h.Will The saturated NH of reactant4Cl aqueous solution (100mL) processes, and extracts with DCM (100mL).Organic layer is separated, is dried (MgSO4) And concentrate in a vacuum.By column chromatography (SiO2, 0-10%EtOAc/ hexane class) and purification residue, obtain as yellow oil Title compound (4.40g, 79%).1H NMR(400MHz,CDCl3)δ7.50(d,1H),7.20-7.10(m,3H),5.22 (m,1H),4.15(q,2H),2.50(m,2H),2.30(m,2H),2.35(s,3H),1.25(t,3H)。
Intermediate 16
1-[(4-methoxyphenyl) methyl]-5-(o-tolyl) pyrrolidin-2-one
(4-methoxyphenyl) first is added in the intermediate 15 (4.40g, 19.8mmol) solution in toluene (20mL) Amine (27.1g, 198.0mmol), and reactant is heated in sealed tube 150 DEG C of holding 18h.Reactant is cooled down and uses Water (50mL) and DCM (50mL) process, and separated by organic layer, be dried (MgSO4) and concentrate in a vacuum.Pass through column chromatography (SiO2, 0-35%EtOAc/ hexane class) and purification residue, obtain the title compound (3.20g, 55%) as white solid.1H NMR(400MHz,CDCl3)δ7.25-7.1(m,4H),6.95(d,2H),6.8(d,2H),5.1(d,1H),4.65(m,1H), 5.8(s,3H),3.4(d,2H),2.45-2.3(m,4H),2.1(s,3H)。LCMS(ES+)296.0(M+H)+。
Intermediate 17
5-(o-tolyl) pyrrolidin-2-one
By the intermediate 16 (3.2g, 10.0mmol) solution in TFA (25mL) in sealed tube 150 DEG C of heating 18h.The reactant mixture of cooling is concentrated in a vacuum.By column chromatography (SiO2, 0-3%MeOH/DCM) and purification remnants Thing, obtains the title compound (1.5g, 79%) as yellow solid.1H NMR(400MHz,CDCl3)δ7.20-7.10(m, 4H),4.85(m,1H),3.50(m,2H),2.25(s,3H),2.20(m,2H)。LCMS(ES+)176.0(M+H)+。
Intermediate 18
1-(5-bromo-2-nitro-phenyl)-5-(o-tolyl) pyrrolidin-2-one
By method A, prepare title compound from intermediate 17 (0.75g, 4.28mmol) and the bromo-Nitrobenzol of the fluoro-4-of 2- (0.50g, 31%).1H NMR(400MHz,CDCl3)δ7.80(d,1H),7.50(d,1H),7.40(d,1H),7.15(m,3H), 7.05(s,1H),5.50(m,1H),2.60-2.70(m,3H),2.35(s,3H),2.10(m,1H)。LCMS(ES+)375.0/ 377.0(M+H)+。
Intermediate 19
4-hydroxy-4-phenyl-ethyl n-butyrate.
Title compound is prepared in the way of similar with intermediate 15.At-78 DEG C to benzaldehyde (1.00g, 9.43mmol) Solution in DCM (30mL) adds TiCl4(15.0mL, 15.0mmol, the 1M solution in DCM).Add (1-ethyoxyl Ring propoxyl group)-the trimethyl-silane (2.90g, 14.10mmol) solution in DCM (20mL), and reactant is stirred at-78 DEG C Mix 30min and warm to room temperature holding 18h.Reactant is used saturated NH4Cl aqueous solution (20mL) processes, and with DCM (20mL) Extraction.Organic layer is separated, is dried (MgSO4) and concentrate in a vacuum.By column chromatography (SiO2, 0-10%EtOAc/ hexane Class) purification residue, obtain the title compound (1.60g, 84%) as yellow oil.1H NMR(400MHz,CDCl3)δ 7.30-7.20(m,5H),4.95(m,1H),4.10(q,2H),2.45-2.30(m,4H),1.25(t,3H)。
Intermediate 20
1-[(4-methoxyphenyl) methyl]-5-phenyl-pyrrolidin-2-ketone
(4-methoxyphenyl) first is added in the intermediate 19 (2.00g, 9.61mmol) solution in toluene (20mL) Amine (13.20g, 96.5mmol), and reactant is heated in sealed tube 150 DEG C of holding 18h.Reactant is cooled down and uses Water (50mL) and DCM (50mL) process, and separated by organic layer, be dried (MgSO4) and concentrate in a vacuum.Pass through column chromatography (SiO2, 0-35%EtOAc/ hexane class) and purification residue, obtain the title compound (2.0g, 74%) as yellow solid.1H NMR(400MHz,CDCl3)δ7.30-7.40(m,3H),7.15(d,2H),7.00(d,2H),6.80(d,2H),5.05(d, 1H),4.40(m,1H),3.80(s,3H),3.40(d,1H),2.50-2.35(m,3H),1.9(m,1H)。LCMS(ES+)282.0 (M+H)+。
Intermediate 21
5-Phenylpyrrolidine-2-ketone
By the intermediate 20 (2.00g, 7.11mmol) solution in TFA (15mL) in sealed tube 150 DEG C of heating 18h.By reactant mixture cooling and concentrate in a vacuum.By column chromatography (SiO2, 0-3%MeOH/DCM) and purification remnants Thing, obtains the title compound (0.80g, 70%) as yellow solid.1H NMR(400MHz,CDCl3)δ8.10(br s, 1H),7.30-7.40(m,5H),4.65(m,1H),2.50(m,1H),2.20(m,2H),1.75(m,1H)。LCMS(ES+) 162.0(M+H)+。
Intermediate 22
1-(5-bromo-2-nitro-phenyl)-5-phenyl-pyrrolidin-2-ketone
By method A, prepare title compound from intermediate 21 (0.50g, 3.10mmol) and the bromo-Nitrobenzol of the fluoro-4-of 2- (0.25g, 23%).1H NMR(400MHz,CDCl3)δ7.80(d,1H),7.30-7.40(m,6H),7.10(s,1H),5.15 (m,1H),2.60-2.70(m,3H),2.20(m,1H)。LCMS(ES+)361.0/362.0(M+H)+。
Intermediate 23 (method B)
7-bromo-1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
In the intermediate 22 (0.50g, 1.38mmol) solution in AcOH (5mL) add iron powder (0.39g, 6.94mmol).Reactant is heated to backflow and keeps 18h.Reactant mixture is filtered through kieselguhr and concentrates in a vacuum. Residue is used saturated NaHCO3Aqueous solution processes, and extracts with EtOAc (10mL).By organics washed with water (10mL) and saline (10mL) washing, separates organic layer, is dried (MgSO4) and concentrate in a vacuum.By column chromatography (SiO2, the ammonia of 0-3% Solution/DCM in methanol) purification residue, obtain title compound (0.38g, 87%).1H NMR(400MHz,CDCl3)δ 7.60(d,1H),7.45-7.40(m,4H),7.35-7.30(m,2H),6.90(s,1H),5.40(m,1H),3.20-3.05(m, 3H),2.50(m,1H)。LCMS(ES+)312.0/314.0(M+H)+。
Intermediate 24
(E/Z)-1-(difluoro-methoxy)-2-(2-nitroethylene base) benzene
Add in 2-(difluoro-methoxy) benzaldehyde (10g, 57.8mmol) solution in AcOH (30mL) at 10 DEG C Nitromethane (7.05g, 115.6mmol) and ethylenediamine (1.73g, 28.9mmol).Reactant mixture is heated 18h at 50 DEG C. After reaction terminates, add icy water, and mixture is stirred vigorously 1h.Precipitate is filtered, washes with water and in vacuum In be dried, obtain the title compound (11g, 92%) as yellow solid.1H NMR(400MHz,CDCl3)8.18(d, J13.6Hz,1H),7.49-7.71(m,3H),7.22-7.31(m,2H),6.45-6.81(t,1H)。
Intermediate 25
N-(1-(2-(difluoro-methoxy) phenyl)-2-nitro-ethyl) azanol
In the intermediate 24 (11.5g, 53.48mmol) solution in EtOH (40mL), oxammonium hydrochloride. is added at 0 DEG C (7.38mg, 106.9mmol) and triethylamine (14.61mL, 106.9mmol).Reactant mixture is stirred at room temperature 18h.Add Water, with EtOAc extraction and concentrates in a vacuum.By column chromatography (SiO2, 0-65%EtOAc/ hexane class) and purification residue, Obtain the title compound (9g, 77%) as yellow oil.1H NMR(400MHz,CDCl3)7.36-7.41(m,2H),7.16- 7.25(m,2H),6.41-6.77(t,1H),5.12(q,J 8.0Hz,1H),4.99(m,1H),4.71(q,J12.8Hz,1H)。
Intermediate 26
1-(2-(difluoro-methoxy) phenyl) ethane-1,2-diamidogen
In the intermediate 25 (6g, 24.19mmol) solution in MeOH (150mL), 10% palladium on carbon is added at 0 DEG C (1.5g).Reactant mixture is stirred at room temperature 18h under nitrogen atmosphere (100psi pressure).By reactant mixture through kieselguhr Bed filters, and is washed by filter cake MeOH, and filtrate is concentrated in a vacuum, obtains the title compound as faint yellow oil (4.7g, 80%).1H NMR(400MHz,DMSO-d6)δ7.60(d,J 6.8Hz,1H),7.20-7.00(m,6H),4.03(q,J 11.2Hz,1H),2.83(dd,J 16.4Hz,1H),2.44(dd,J 12.4Hz,1H),1.80(bs,2H)。LCMS(ES+)RT 1.31min,203(M+H)+。
Intermediate 27
(2-amino-2-(2-(difluoro-methoxy) phenyl) ethyl) t-butyl carbamate
At 0 DEG C in the intermediate 26 (4g, 19.7mmol) solution in anhydrous DCM (50mL), add triethylamine (2.7mL, 19.7mmol) and Bis(tert-butoxycarbonyl)oxide (4.3g, 19.7mmol).Reactant mixture is stirred at room temperature 3h.Add Mixture DCM is also extracted by water.Organic layer water and saline are washed, is dried (Na2SO4) and concentrate in a vacuum.By system Standby type TLC (MeOH of 5% solution in DCM) purification residue, obtain title compound as white solid (3.1g, 52%).1H NMR(400MHz,CDCl3)7.43(d,J 7.6Hz,1H),7.19-7.28(m,2H),7.07(d,J 7.6Hz, 1H),6.38-6.75(t,1H),4.85(bs,1H),4.35(m,1H),3.36(m,2H),1.80(bs,2H),1.39(s,9H)。 LCMS(ES+)RT 2.09min,303(M+H)+。
Intermediate 28
4-(2-(difluoro-methoxy) phenyl)-2-oxo-imidazole alkane-1-t-butyl formate
In the intermediate 27 (6g, 19.8mmol) solution in DCM (80mL) add 1,1 '-carbonyl dimidazoles (3.8g, 23.83mmol), and by reactant mixture 4h is stirred at room temperature.Reactant mixture is concentrated in a vacuum, and passes through column chromatography (SiO2, 0-50%EtOAc/ hexane class) and purification residue, obtain the title compound (4.2g, 64%) as yellow oil.1H NMR(400MHz,CDCl3)7.50(t,J 7.2Hz,1H),7.36-7.24(m,2H),7.10(d,J 8Hz,1H),6.76- 6.39(t,1H),5.08(dd,J 16Hz,1H),4.27(t,J 10Hz,1H),3.58(dd,J 10.8Hz,1H),1.60(s, 9H)。
Intermediate 29
3-(the bromo-4-of 5-fluoro-2-nitrobenzophenone)-4-(2-(difluoro-methoxy) phenyl)-2-oxo-imidazole alkane-1-formic acid uncle Butyl ester
Title compound is prepared with the method similar with method A.To intermediate 28 (2.1g, 6.4mmol) at DMF (15mL) In solution in add Cs2CO3(6.2g, 19.2mmol) and 2,5-bis-fluoro-4-bromo nitrobenzene (1.7g, 7.04mmol).By content Thing heats 3h at 60 DEG C in sealed tube.Reactant mixture is used frozen water quencher, and aqueous layer EtOAc is extracted.Will Organic layer is dried (Na2SO4) and concentrate in a vacuum.By post (SiO2, 0-30%EtOAc/ hexane class) and purification residue, To the title compound (2.6g, 74%) as yellow solid.1H NMR(400MHz,CDCl3)δ7.77(d,J 8Hz,1H), 7.63(d,J 7.6Hz,1H),7.24-7.38(m,3H),7.14(d,J 8Hz,1H),6.76-6.39(t,1H),5.61(t,J 16.8Hz,1H),4.38(t,J 20Hz,1H),3.79(dd,J 10Hz,1H),1.60(s,9H)。
Intermediate 30
1-(2-amino-5-bromo-4-fluoro-phenyl)-5-[2-difluoro-methoxy) phenyl] imidazolidin-2-one
In the intermediate 29 (500mg, 0.91mmol) solution in AcOH (6mL) add iron powder (252mg, 4.58mmol), and at 100 DEG C 18h is stirred.Reactant is filtered through bed of diatomaceous earth, and filtrate is concentrated in a vacuum.Pass through Column chromatography (SiO2, 0-5%MeOH/DCM) purification residue, obtain title compound as pale solid (210mg, 55%).1H NMR(400MHz,CDCl3)δ7.77(d,J 10Hz,1H),7.54(d,J 7.6Hz,1H),7.26-7.10(m, 3H),7.08(t,J 16Hz,1H),6.69-6.32(t,1H),5.76(q,J 17Hz,1H),5.00(bs,2H),4.08(t,J 18Hz,1H),3.44(t,J 16.8Hz,1H)。LCMS(ES+)RT 2.17min,416.1(M+H)+。
Intermediate 31
The bromo-3-of 6-(2-(difluoro-methoxy) phenyl)-7-fluoro-2,3-dihydro-1H-benzo [d] imidazo [1,2-a] imidazoles
Title compound is prepared by the variant of method B.To intermediate 30 (150mg, 0.36mmol) in toluene (5mL) Solution in add P2S5(160mg,0.72mmol).Reflux 4h by reactant mixture.Reactant mixture is used saturated NaHCO3Water Solution quencher, and aqueous layer EtOAc is extracted.By the organic layer use water merged, saline washing and dry (Na2SO4), and Concentrate in a vacuum.By preparative TLC (DCM/MeOH 95/5) purification residue, obtain the title as pale solid Compound (50mg, 35%).1H NMR(400MHz,CDCl3)δ7.40(t,J 14.4Hz,1H),7.26-7.10(m,4H), 6.84-6.46(t,1H),5.86(t,J 15Hz,1H),5.60(bs,1H),4.58(t,J 18Hz,1H),3.89(dd,J 9.6Hz,1H)。LCMS(ES+)RT 2.06min,398/400.0(M+H)+。
Intermediate 32
3-(5-bromo-2-nitrobenzophenone)-4-(2-(difluoro-methoxy) phenyl)-2-oxo-imidazole alkane-1-t-butyl formate
Title compound is prepared with the method similar with method A.To intermediate 28 (200mg, 0.6mmol) at DMF (5mL) In solution in add Cs2CO3(586mg, 1.8mmol) and 2-fluoro-4-bromo nitrobenzene (147mg, 0.67mmol).Reaction is mixed Compound heats 3h at 60 DEG C in sealed tube.Reactant mixture is carried out quencher by adding frozen water, and aqueous layer is used EtOAc extracts.By the organic layer use water merged, saline washing, it is dried (Na2SO4), and concentrate in a vacuum.Pass through column chromatography (SiO2, 0-30%, EtOAc/ hexane class) purification residue, obtain title compound as yellow solid (250mg, 77%).1H NMR(400MHz,CDCl3)δ7.82(d,J 8.4Hz,1H),7.66(d,J 7.6Hz,1H),7.42-7.21(m, 4H),7.14(d,J 8.4Hz,1H),6.77-6.41(t,1H),5.66(t,J 17.2Hz,1H),4.38(t,J 20Hz,1H), 3.76(t,J 10.4Hz,1H),1.56(s,9H)。
Intermediate 33
1-(the bromo-phenyl of 2-amino-5-)-5-[2-(difluoro-methoxy) phenyl] imidazolidin-2-one
In the intermediate 32 (500mg, 0.94mmol) solution in AcOH (5mL) add iron powder (260mg, 4.73mmol), and by reactant mixture 4h is heated at 100 DEG C.Solvent is concentrated in a vacuum, by residue diluted with water, and Use saturated NaHCO3PH is adjusted to 7 by aqueous solution.Mixture is filtered through bed of diatomaceous earth, and filtrate is extracted with EtOAc.Will Organic layer use water, saline washing and the dry (Na merged2SO4), and concentrate in a vacuum.By column chromatography (SiO2, 0-5% MeOH/DCM) purification residue, obtains the title compound (300mg, 80%) as pale solid.1H NMR(400MHz, DMSO-d6)δ7.70(d,J 8.4Hz,1H),7.54(d,J 18Hz,1H),7.42-7.11(m,4H),6.90(m,1H),6.62 (d,J 8.8Hz,1H),5.71(t,J 15.6Hz,1H),3.86(t,J 16.4Hz,1H),3.15(t,J 15.2Hz,1H)。 LCMS(ES+)RT 2.12min,398.2(M+H)+。
Intermediate 34
The bromo-3-of 6-(2-(difluoro-methoxy) phenyl)-2,3-dihydro-1H-benzo [d] imidazo [1,2-a] imidazoles
Title compound is prepared by the variant of method B.To intermediate 33 (500mg, 1.25mmol) in toluene (5mL) Solution in add P2S5(279mg,1.25mmol).Reflux 4h by reactant mixture.Reactant mixture is used saturated NaHCO3Water Solution quencher, and aqueous layer EtOAc is extracted.The organic layer of merging is dried (Na2SO4), and concentrate in a vacuum.Logical Cross column chromatography (SiO2, 0-2%MeOH/DCM) purification residue, obtain title compound as pale solid (55mg, 11%).1H NMR(400MHz,CDCl3)δ7.40(t,J 14.4Hz,1H),7.30-7.15(m,5H),7.09(t,J 7.2Hz, 1H),6.86-6.45(t,1H),5.86(t,J 14.8Hz,1H),5.10(bs,1H),4.56(t,J 18Hz,1H),3.87(t, J 14.8Hz,1H)。LCMS(ES+)RT 2.48min,380.0/382.0(M+H)+。
Intermediate 35
(5R or S)-1-(the bromo-4-of 5-fluoro-2-nitro-phenyl)-5-[2-(difluoro-methoxy) phenyl] pyrrolidin-2-one
Title compound is prepared with the method similar with method A.To intermediate 12 (5.0g, 22.0mmol) at MeCN (48mL) solution in adds 4-bromo-2,5-difluoro nitrobenzene (5.76g, 23.2mmol) and Cs2CO3(15.77g, 47.93mmol).Mixture is stirred 18h at 40 DEG C, and concentrates in a vacuum.By residue saline treatment and divide with EtOAc Join.Aqueous layer EtOAc is extracted, the organic facies of merging is dried (MgSO4), filter and concentrate in a vacuum.By remnants Thing is further purified for next step without any.LCMS(ES+)RT 5.0min,445.0/447.0(M+H)+。
Intermediate 36
1-(the bromo-4-of 5-fluoro-2-nitro-phenyl)-5-[2-(difluoro-methoxy) phenyl] pyrrolidin-2-one
To intermediate 9 (3.36g, 14.8mmol) and 4-bromo-2, the solution of 5-difluoro nitrobenzene (7.04g, 29.6mmol), (3.31g, 50%) is carried out by method A.1H NMR(DMSO-d6,400MHz)δ:8.10(d,J 8.3Hz,1H),7.60(m, 2H),7.35(m,2H),7.23(m,2H),5.84(m,1H),2.62(m,2H),2.01(m,2H)。LCMS(ES+)RT 1.52min,445.0/447.0(M+H)+。
Intermediate 37
4-methyl piperidine-1,4-dioctyl phthalate-1-the tert-butyl group-4-ethyl ester
N-Boc-piperidine-4-ethyl formate (10.00g, 36.92mmol) is dissolved in THF (100mL) and is cooled to- 78℃.Add LDA (47mmol, 23mL), and reactant is stirred 1h.It is subsequently adding iodomethane (81.25mmol, 5.08mL), And reactant is stirred other 1h, then remove cooling bath, and reactant is warmed to room temperature holding 30min.Reactant is used Saturated NH4Cl aqueous solution quencher also distributes with EtOAc, by organic substance extraction and dry (MgSO4), and concentrate in a vacuum (quantitatively Yield).1H NMR(400MHz,DMSO-d6)δ:4.11(q,J 7.1Hz,2H),3.61(dt,J 13.4Hz,J 4.5Hz,2H), 2.95(d,J 0.3Hz,2H),1.91(d,J 13.6Hz,2H),1.39(s,9H),1.31(m,2H),1.19(m,3H),1.15 (s,3H)。
Intermediate 38
4-methyl piperidine-4-Ethyl formate；Hydrochlorate
It is dissolved in 1,4-bis-to intermediate 37 (11.0g, 40.5mmol) at 0-5 DEG CIn solution in alkane (30.0mL) (15.2mL, 4M are at 1,4-bis-to add HClSolution in alkane).Mixture is warmed to room temperature and stirs 18h.Reaction is mixed Compound concentrates in a vacuum and is washed by residue with diethyl ether, obtain title compound as orange solids (5.02g, 59.6%).1H NMR(DMSO-d6)δ:9.00(m,1H),4.14(q,J 6.8Hz,2H),3.16(m,2H),2.82(m,2H), 2.08(d,J 14.4Hz,2H),1.65(m,2H),1.22(m,6H)。
Intermediate 39
[2-(4-ethoxy carbonyl-4-methyl isophthalic acid-piperidyl) pyrimidine-5-base] boric acid
By 2-chloropyrimide-5-boric acid (3.95g, 24.2mmol), intermediate 38 (5.03g, 24.2mmol) and triethylamine (60.6mmol, 8.50mL) mixture in EtOH (50mL) heats 5h at 70 DEG C.By reactant cooling and at water (100mL) And distribute between EtOAc (100mL).Aqueous layer separate and use other EtOAc (2 × 100mL) heavily extract.By organic lamination And, and wash with saline (100mL), it is then peeled off, is dried (MgSO4), under reduced pressure filter and concentrate in a vacuum, made Title compound (quantitative yield) for brown foam.LCMS(ES+)RT 1.23min 294.0(M+H)+。
Intermediate 40
[2-[(1R, 5S)-8-methoxycarbonyl-3-azabicyclo [3.2.1] octane-3-base] pyrimidine-5-base] boric acid
By (1R, 5S)-3-tert-butoxycarbonyl-3-azabicyclo [3.2.1] octane-8-formic acid (9.0g, 35.3mmol) It is suspended in HCl solution (solution in MeOH of 2.25M), and reactant is heated to backflow holding 4h.Reactant is cold But to room temperature, concentrate the most in a vacuum, obtain white solid.Addition (2-chloropyrimide-5-base) boric acid (5.58g, 35.2mmol), and by mixture it is suspended in EtOH (130mL).Add triethylamine (9.90mL, 70.5mmol), and will reaction Thing heats 5h at 80 DEG C.Reactant is cooled to room temperature, is subsequently adding water (30mL).Reactant mixture is concentrated into about 1/3 body Long-pending, it is subsequently adding more water (100mL).Pale solid is precipitated out, is filtered, and wash with water (2 × 30mL), Obtain the title compound (8.9g, 86% yield) as pale powder.1H NMR(300MHz,DMSO-d6)δppm 8.59 (2H,s),8.02(2H,s),4.45(2H,dd,J 13.1,3.4Hz),3.62(3H,s),2.98(2H,br d,J 12.4Hz), 2.77(1H,s),2.59(2H,br s),1.66-1.63(2H,m),1.38-1.33(2H,m)。LCMS(ES+)RT0.97min 292.0(M+H)+。
Intermediate 41 and 42
Enantiomer 1:(5R or S)-5-Phenylpyrrolidine-2-ketone and enantiomer 2:(5S)-5-Phenylpyrrolidine- 2-ketone
By under the conditions of SFC Chiralpak IC (50*264mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%EtOH, injects 7.6mL, and solution concentration is 100g/L) upper purification intermediate 20, separate title compound.Collect and first wash De-enantiomer (RT 6.2min), and described fraction is evaporated to obtain enantiomer 1 (5R or S)-5-phenylpyrrole Alkane-2-ketone (is arbitrarily classified as (5R) enantiomer, 5.34g).Collect the enantiomer (RT 9.0min) of the second eluting, and The evaporation of described fraction (is arbitrarily classified as (5S) enantiomerism obtaining enantiomer 2 (5S or R)-5-Phenylpyrrolidine-2-ketone Body, 5.58g).1H NMR(400MHz,CDCl3)δ7.33(m,5H),6.34(m,1H),4.75(t,1H,J 7.0Hz),2.49 (m,3H),1.97(m,1H)。LCMS(ES+)RT 3.14min,162.2(M+H)。
Intermediate 43
Enantiomer 1:(5R or S)-1-(5-bromo-2-nitro-phenyl)-5-phenyl-pyrrolidin-2-ketone
Title compound is prepared with the method similar with method A.To intermediate 42 (5.34g, 33.1mmol) at MeCN (400mL) solution in adds the bromo-2-of 4-fluoro-1-nitro-benzene (8.75g, 39.8mmol) and Cs2CO3(23.7g, 72.9mmol), and by reactant 20h is heated at 75 DEG C.Add water, and mixture EtOAc is extracted 3 times.By having of merging Machine is dried (MgSO mutually4) and concentrate in a vacuum, obtain title compound (11.9g, 100%), by it without further purification Ground is for next step.1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.78(d,1H,J 8.7Hz),7.41(m,5H), 7.13(d,1H,J 1.6Hz),5.16(t,1H,J 7.4Hz),2.68(m,3H),2.22(m,1H)。LCMS(ES+)RT 4.74min,361/363(M+H)。
Intermediate 44
Enantiomer 1:(1R or S)-7-bromo-1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method B, prepare title compound (8.2g, 84%) from intermediate 43 (33.1mmol).LCMS(ES+)RT 4.84min,313.0/315.0(M+H)+。
Intermediate 45
2-[2-(difluoro-methoxy) phenyl] thiazolidin-4-one
Addition it is dissolved in the solution in toluene (30mL) to 2-(difluoro-methoxy) benzaldehyde (9.87g, 57.4mmol) 2-sulfanyl acetic acid (6.87g, 74.6mmol) and (NH4)2CO3(28.66g,298.3mmol).By mixture 110 DEG C of stirrings 18h also concentrates in a vacuum.Residue is ground together with EtOAc.The precipitate obtained is filtered, obtains as white solid Title compound (8.07g, 57%).LCMS(ES+)RT 3.34min,246.1(M+H)。
Intermediate 46 and 47
Enantiomer 1:(2R or S)-2-[2-(difluoro-methoxy) phenyl] thiazolidin-4-one；Enantiomer 2 (2S Or R)-2-[2-(difluoro-methoxy) phenyl] thiazolidin-4-one
By under the conditions of SFC Chiralpak AD (50*216mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%EtOH keeps 1.7min, and then 40%EtOH keeps 3min, the solution of the 100g/L concentration of injection 4.45mL) go up in purification Mesosome 45, separates title compound.Collect the enantiomer (RT 1.7min) of first eluting, and by the evaporation of described fraction with Obtain described compound (being arbitrarily classified as (2R) enantiomer).Collect the enantiomer (RT 2.7min) of the second eluting, and Described fraction is evaporated to obtain described compound (being arbitrarily classified as (2S) enantiomer).
Intermediate 48
3-(5-bromo-2-nitro-phenyl)-2-[2-(difluoro-methoxy) phenyl] thiazolidin-4-one
By method A, from intermediate 45 (3.03g, 12.3mmol) and the bromo-2-of 4-fluoro-1-nitro-benzene (5.44g, 24.7mmol) prepare title compound (3.76g, 68.0%).LCMS(ES+)RT 4.5min,445.0/447.0(M+H)+。
Intermediate 49
The bromo-1-of 7-[2-(difluoro-methoxy) phenyl]-1,3-thiazoline also [3,4-a] benzimidazole
By method B, prepare title compound from intermediate 48 (3.01g, 6.76mmol) and ferrum (1.89g, 33.8mmol) Thing.Residue is further purified for next step without any.LCMS(ES+)RT 4.54min,397.1/399.1(M+H)+。
Intermediate 50
5-ethyoxyl pyrrolidin-2-one
0 DEG C add in the butanimide (50g, 0.50mol) solution in EtOH (1.2L) sodium borohydride (48g, 1.3mol), and last 3h and be slowly added into 1M H2SO4Solution (100mL) in EtOH.Then reactant mixture is cooled down To-50 DEG C, and use 6M H2SO4Solution is acidified to pH 2.Reactant mixture is stirred at room temperature 3h, and uses the KOH of 2M to exist Solution in EtOH neutralizes.Reactant is concentrated in a vacuum.By residue stirring 30min in chloroform (1.0L), and pass Bed of diatomaceous earth filters.Filtrate is concentrated in a vacuum, and by column chromatography (SiO2, 0-2%MeOH/DCM) and purification residue, Obtain the title compound (25g, 38%) as white solid.1H NMR(400MHz,CDCl3)δ7.8(bs,1H),4.9(d, 1H),3.5-3.6(m,1H),3.3-3.4(m,1H),2.4-2.5(m,1H),2.2-2.3(m,2H),2-2.1(m,1H),1.2 (t,3H)。LCMS(ES+)(M+H)+130。
Intermediate 51
[2-(morpholine-4-base) pyrimidine-5-base] boric acid
By (2-chloropyrimide-5-base) boric acid (1g, 6.32mmol), morpholine (2.19mL, 25.26mmol) and triethylamine (0.9mL, 6.32mmol) solution in ethanol (25mL) stirs 1h at 20 DEG C.Water (50mL) is slowly added into reaction mixing To form precipitate in thing, be collected by filtration, obtain as breast cream solid (cream solid) titled Compound (950mg, 70%).δH(250MHz,DMSO-d6)8.63(s,2H),8.05(s,2H),3.68(ddd,J 23.4,5.7, 3.9Hz,8H)。LCMS(ES+)210(M+H)+。
Intermediate 52
5-(2-methoxyphenyl) pyrrolidin-2-one
Under an inert atmosphere, dry magnesium metal (540mg, 23.25mmol) is suspended in anhydrous THF (15mL).? 70 DEG C, succeedingly add glycol dibromide (0.1mL) and 2-bromine methoxybenzene (2.9mL, 23.25mmol).By reactant 70 DEG C stirring 1h, be subsequently cooled to 0 DEG C.Add the intermediate 50 (1g, 7.75mmol) solution in THF (10mL).Reaction is mixed Compound stirs 5h at 70 DEG C, is then carefully added into water (10mL) and AcOH (5mL).Continue to be stirred at room temperature 30min, and Extraction in EtOAc (3 × 50mL).Organic layer is dried (Na2SO4), concentrate in a vacuum.By column chromatography (SiO2, 0-2% MeOH/DCM) purification residue, obtain 5-(2-methoxyphenyl) pyrrolidin-2-one as white solid (600mg, 40%).1H NMR(400MHz,CDCl3)δ7.30(m,2H),7.00-6.90(m,2H),5.90(bs,1H),5.10(t,1H), 3.90(s,3H),2.70-2.32(m,3H),2(m,1H)。
Intermediate 53
1-(the bromo-4-of 5-fluoro-2-nitrobenzophenone)-5-(2-methoxyphenyl) pyrrolidin-2-one
Title compound is prepared with the method similar with method A.To intermediate 52 (600mg, 3.14mmol) at DMF (10mL) in the solution in add cesium carbonate (3.06g, 9.42mmol), 4-bromo-2,5-difluoro nitrobenzene (747mg, 3.14mmol, 1 equivalent), and heat 18h at 90 DEG C.In room temperature, slurry is poured in icy water, and with EtOAc (3 × 70mL) extraction.Organic layer icy water and saline are washed, is dried (Na2SO4), concentrate in a vacuum.Pass through column chromatography (SiO2, 0-30%EtOAc/ hexane class) and purification residue, obtain 1-(the bromo-4-of the 5-fluoro-2-Nitrobenzol as yellow solid Base)-5-(2-methoxyphenyl) pyrrolidin-2-one (600g, 46%).1H NMR(400MHz,CDCl3)δ7.70(d,1H), 7.40-7.22(m,3H),7.00-6.90(m,2H),5.60(t,1H),3.90(s,3H),2.80-2.60(m,2H),2.30- 2.20(m,2H)。LCMS(ES+)409.0/411.0(M+H)+。
Intermediate 54
The fluoro-1-of the bromo-6-of 7-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method B, prepare title compound from intermediate 53 (3g, 7.3mmol) and iron powder (1.3g, 22mmol) (1.5g, 57%).1H NMR(400MHz,CDCl3)δ7.50(d,1H),7.30(t,1H),7.10(d,1H),6.90(d,1H), 6.82(t,1H),6.90(d,1H),5.90(t,1H),3.90(s,3H),3.20-3.00(m,3H),2.60-2.50(m,1H)。 LCMS(ES+)361.0/363.0(M+H)+。
Intermediate 55 and 56
Enantiomer 1 (1R or the S)-7-fluoro-1-of bromo-6-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole；Enantiomer 2 (1S or the R)-7-fluoro-1-of bromo-6-(2-methoxyphenyl)-2,3-dihydro-1H-pyrrolo- [1,2-a] benzimidazole
By under the conditions of SFC Chiralpak AD (50*216mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 25%MeOH, the solution of the 10g/L concentration of injection 25mL) upper chirally purified 2g intermediate 54, separate title compound.Collect head The enantiomer (RT 3.4min) of first eluting, and described fraction is evaporated to obtain 863mg intermediate 55.Collect second to wash De-enantiomer (RT 5.3min), and described fraction is evaporated to obtain 834mg intermediate 56.
Intermediate 57
4-(2-chlorphenyl)-4 hydroxybutyric acid ethyl ester
Title compound is prepared by the method similar with intermediate 1.-78 DEG C to 2-chlorobenzaldehyde (1.5g, 10.71mmol) solution in DCM (12mL) is added dropwise over TiCl4(11.8mL, the 1M solution in DCM) and [(1-second Epoxide cyclopropyl) epoxide] (trimethyl) silane (2.6mL, 12.8mmol).After-78 DEG C of stirring 30min, by reactant temperature Heat keeps 18h to room temperature.By reactant by adding saturated NH4Cl aqueous solution (5mL) quencher.By aqueous layer with DCM (2 × 10mL) extract and be dried (Na2SO4), concentrate in a vacuum.By column chromatography (SiO2, 0-10%EtOAc/ hexane class) and purification Residue, obtains the title compound (1.4g, 60%) as yellow oil.LCMS(ES+)243.0(M+H)+。
Intermediate 58
The bromo-4-of 5-fluoro-2-nitroaniline
By bromo-for the 1-2,5-bis-fluoro-4-Nitrobenzol (2g, 8.43mmol) solution in the methanol solution (25mL) of ammonia close Close in test tube and heat 18h at 60 DEG C.Reactant is concentrated in a vacuum, and by column chromatography (SiO2, 0-30%EtOAc/ is own Alkanes) purification residue, obtain the title compound (1.4g, 73%) as yellow solid.1H NMR(400MHz,CDCl3) 7.90(d,1H),7.10(d,1H),5.98(bs,2H)。
Intermediate 59
1-(the bromo-4-of 5-fluoro-2-nitrobenzophenone)-5-(2-chlorphenyl) pyrrolidin-2-one
In sealed tube, by intermediate 57 (200mg, 0.82mmol), intermediate 58 (287mg, 1.23mmol) and 3 Dense H2SO410h is heated at 160 DEG C in toluene.Reactant is cooled to room temperature and adds water (10mL).Aqueous layer is used EtOAc (2 × 10mL) extracts, and by the organic layer use water merged, saline washing, is dried (Na2SO4), concentrate in a vacuum.Logical Cross column chromatography (SiO2, 0-40%EtOAc/ hexane class) and purification residue, obtain the title compound as yellow solid (75mg, 22%).1H NMR(400MHz,CDCl3)δ7.78(d,1H),7.60(d,1H),7.40-7.25(m,4),5.78(m, 1H),2.80-2.65(m,3H),2.15(m,1H)。LCMS(ES+)412.0/414.0(M+H)+。
Intermediate 60
The bromo-1-of 7-(2-chlorphenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method B, prepare titled from intermediate 59 (500mg, 1.21mmol) and iron powder (203mg, 3.64mmol) Compound (300mg, 68%).1H NMR(400MHz,CDCl3)δ7.50(d,2H),7.30-7.20(m,2H),7.10(d,1H), 6.65(d,1H),5.92(m,1H),3.25-3.15(m,3H),2.56(m,1H)。LCMS(ES+)366.0/368.0(M+H)+。
Intermediate 61 and 62
Enantiomer 1:(1R or S) the bromo-1-of-7-(2-chlorphenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] Benzimidazole；Enantiomer 2 (1S or R)-7-bromo-1-(2-chlorphenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] Benzimidazole
By under the conditions of SFC Chiralpak IA (50*266mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%MeOH, the solution of the 30g/L concentration of injection 5.33mL) upper chirally purified 478mg intermediate 60, separate title compound. Collect the enantiomer 1 (RT 6.3min) of first eluting, and described fraction is evaporated to obtain.Intermediate 61.Collect second The enantiomer 2 (RT 8.2min) of eluting, and described fraction is evaporated to obtain intermediate 62.
Intermediate 63
5-(4-fluorophenyl) pyrrolidin-2-one
By the method similar with the operation provided about intermediate 52, prepare title compound.At 60 DEG C to magnesium metal (1.1g, 46.5mmol) solution in anhydrous THF (20mL) lasts 15min and adds glycol dibromide and the 4-fluorine of catalysis The bromobenzene (5.1mL, 46.5mmol) solution in THF (5mL).Reflux 1h by reactant mixture.Reactant is cooled to 0 DEG C, And it is added dropwise over the intermediate 50 (2g, 15.5mmol) solution in anhydrous THF (10mL).By reactant mixture in room temperature 0 DEG C stirring 1h (stirred r.t.for 1h at 0 DEG C), be then refluxed for 5h.Reactant mixture is cooled down and is carefully added into water (4mL) AcOH (6mL), it is subsequently added.Continue to be stirred at room temperature 30min, and extraction in EtOAc (3 × 50mL).By organic layer Through Na2SO4It is dried, concentrates in a vacuum.By column chromatography (SiO2, 0-2%MeOH/DCM) and purification residue, obtain conduct 5-(4-fluorophenyl) pyrrolidin-2-one (1.3g, 47%) of white solid.1H NMR(400MHz,CDCl3)δ7.27(dd,J 8.7,4.9Hz,2H),7.05(t,J 8.5Hz,2H),6.21(s,1H),4.74(t,J 7.0Hz,1H),2.68-2.33(m, 3H),1.94(dq,J 11.9,8.1Hz,1H)。LCMS(ES+)(M+H)+180。
Intermediate 64
1-(the bromo-4-of 5-fluoro-2-nitrobenzophenone)-5-(4-fluorophenyl) pyrrolidin-2-one
Title compound is prepared with the method similar with method A.To intermediate 63 (2.2g, 12.2mmol) in dry DMF (15mL) in the solution in add cesium carbonate (9.98g, 30.7mmol) and 4-bromo-2,5-difluoro nitrobenzene (3.1g, 13.5mmol).Reactant mixture is stirred at room temperature 18h.Reactant mixture is processed by adding water (30mL), and uses EtOAc (4 × 20mL) extracts.Organic layer water and saline are washed, is dried (Na2SO4) and concentrate in a vacuum.By post color Spectrometry (SiO2, 0-50%EtOAc/ hexane class) purification residue, obtain title compound as yellow solid (2.3g, 47%).1H NMR(400MHz,CDCl3) δ 7.73 (dd, J=7.6,2.4Hz, 1H), 7.35 (ddd, J 8.7,5.1,2.4Hz, 2H),7.19(dd,J 6.2,2.4Hz,1H),7.04(tt,J 9.7,2.9Hz,2H),5.17-5.00(m,1H),2.88-2.54 (m,3H),2.30-2.10(m,1H)。
Intermediate 65
The fluoro-1-of the bromo-6-of 7-(4-fluorophenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method B, prepare title compound from intermediate 64 (2.3g, 5.8mmol) and iron powder (975mg, 17.4mmol) Thing (1.5g, 74%).1H NMR(400MHz,CDCl3)δ7.47(d,J 9.2Hz,1H),7.22-7.02(m,4H),6.93(d,J 6.0Hz,1H),5.40(t,J 6.8Hz,1H),3.38-3.01(m,3H),2.54(ddt,J 14.4,11.7,5.1Hz,1H)。 LCMS(ES+)349.0/351.0(M+H)+。
Intermediate 66 and 67
Enantiomer 1:(1S or R) the fluoro-1-of the bromo-6-of-7-(4-fluorophenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] Benzimidazole；Enantiomer 2 (1R or the S)-7-fluoro-1-of bromo-6-(4-fluorophenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] Benzimidazole
By under the conditions of SFC Chiralpak AD (50*216mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 40%EtOH, the solution of the 50g/L concentration of injection 10mL) upper chirally purified 2g intermediate 65, separate title compound.Collect head The enantiomer 1 (RT 1.9min) of first eluting, and described fraction is evaporated to obtain 1.23g intermediate 66.Collect second to wash De-enantiomer 2 (RT 3min), and described fraction is evaporated to obtain 1.19 intermediate 67.
Intermediate 68
1-bromo-2-(methylsulfanyl) benzene
In the NaOH (1.7g, 42.50mmol) solution in EtOH (15mL) add 2-bromine thiophenol (5g, 26.45mmol).Reactant mixture is stirred at room temperature 30min, is subsequently cooled to 0 DEG C, and add iodomethane (2.4mL, 39mmol).Reactant mixture is stirred at room temperature 10h.Reactant mixture frozen water is processed, and extracts with DCM (2 × 20mL) Take.Organic layer water and saline are washed, is dried (Na2SO4), and concentrate in a vacuum.By flash chromatography (SiO2,0- 5%EtOAc/ hexane class) purification residue, obtain the title compound (4.6g, 86%) as yellow oil.LCMS(ES+) 203.0/205.0(M+H)+。
Intermediate 69
5-[2-(methylsulfanyl) phenyl] pyrrolidin-2-one
In the magnesium metal (223mg, 9.30mmol) solution in anhydrous THF (10mL), last 15min at 60-65 DEG C to add Enter glycol dibromide and the intermediate 68 (1.87g, the 9.30mmol) solution in THF (5mL) of catalysis.By reactant mixture Backflow 1h.Reactant is cooled to 0 DEG C, and is added dropwise over intermediate 50 (400mg, 3.10mmol) in anhydrous THF (5mL) Solution.Reactant mixture is stirred 1h in room temperature at 0 DEG C, is then refluxed for 5h.Reactant mixture is cooled down and is carefully added into water (1mL) AcOH (1mL), it is subsequently added.Continue 30min among EtOAcs (3 × 50mL) extraction are stirred at room temperature.By organic layer It is dried (Na2SO4), concentrate in a vacuum.By column chromatography (SiO2, 0-2%MeOH/DCM) and purification residue, obtain conduct The title compound (300mg, 46%) of white solid.1H NMR(400MHz,CDCl3)δ7.35-7.20(m,4H),5.95(bs, 1H),5.20(m,1H),2.70(m,1H),2.44(s,3H),2.40(m,2H),1.95(m,1H)。LCMS(ES+)(M+H)+ 208.0。
Intermediate 70
1-(the bromo-4-of 5-fluoro-2-nitrobenzophenone)-5-[2-(methylsulfanyl) phenyl] pyrrolidin-2-one
By the similar variant of method A, prepare title compound.To intermediate 69 (300mg, 1.44mmol) anhydrous In solution in DMF (6mL) add cesium carbonate (1.4g, 4.32mmol) and 4-bromo-2,5-difluoro nitrobenzene (376mg, 1.59mmol).Reactant mixture is stirred at room temperature 14h.By reactant mixture use water (5mL) process, and with EtOAc (4 × 10mL) extraction.By organic layer use water, saline washing and dry (Na2SO4), concentrate in a vacuum.By column chromatography (SiO2, 0-65%EtOAc/ hexane class) purification residue, obtain the title compound (305mg, 49%) as yellow solid.LCMS (ES+)425.0/427.0(M+H)+。
Intermediate 71
The fluoro-1-of the bromo-6-of 7-[2-(methylsulfanyl) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method B, prepare titled from intermediate 70 (300mg, 0.707mmol) and iron powder (118mg, 2.12mmol) Compound (205mg, 77%).LCMS(ES+)377.0/379.0(M+H)+。
Intermediate 72
The fluoro-1-of the bromo-6-of 7-[2-(methyl sulphonyl) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
In the intermediate 71 (1.9g, 5.03mmol) solution in DCM (25mL), it is added portionwise into m-CPBA at 0 DEG C (2.58g,15.09mmol).Reactant mixture is stirred at room temperature 2h.Add the saturated NaHCO of 5mL3Aqueous solution, and by aqueous solution Layer DCM (2 × 10mL) extraction.By organic layer use water, saline washing and dry (Na2SO4), concentrate in a vacuum.By quickly Chromatography (SiO2, 0-100%EtOAc/ hexane class) and purification residue, obtain the title compound as yellow solid (1.25g, 60%).1H NMR(400MHz,CDCl3)δ8.2(d,1H),7.55-7.60(m,3H),6.82-6.9(m,2H),6.4 (m,1H),3.4(m,1H),3.25(s,3H),3.15-3.21(m,2H),2.5(m,1H)。LCMS(ES+)409.0/411.0(M+ H)+。
Intermediate 73 and 74
Enantiomer 1:(1S or R) the fluoro-1-of the bromo-6-of-7-(2-methylsulfonyl phenyl)-2,3-dihydro-1H-pyrrolo- [1,2-a] benzimidazole；Enantiomer 2 (1R or the S)-7-fluoro-1-of bromo-6-(2-methylsulfonyl phenyl)-2,3-dihydro- 1H-pyrrolo-[1,2-a] benzimidazole
By under the conditions of LC Chiralpak AD (100*500mm*mm, flow velocity 300mL/min, 30 DEG C, CO2+ heptan Alkane-i-PrOH (1:1), the solution of the 1g/L concentration of injection 972mL) upper chirally purified 2.35g intermediate 72, separate title compound Thing.Collect the enantiomer 1 (RT 25min) of first eluting, and described fraction is evaporated to obtain intermediate 73.Collect the The enantiomer 2 (RT 47min) of two eluting, and described fraction is evaporated to obtain intermediate 74.
Intermediate 75
5-[2-(trifluoromethyl) phenyl] pyrrolidin-2-one
By the method similar with the method described about intermediate 52 in the past, prepare title compound.60-65 DEG C to Magnesium metal (2.78g, 116mmol) lasts 20min and adds the glycol dibromide of catalysis in the solution in anhydrous THF (80mL) With the 2-5 bromine benzotrifluoride (26g, 116mmol) solution in THF (10mL).Reflux 1h by reactant mixture.Reactant is cold But to 0 DEG C, and it is added dropwise over the intermediate 50 (5g, 38.7mmol) solution in anhydrous THF (10mL).Reactant mixture is existed Room temperature stirs 1h at 0 DEG C, is then refluxed for 5h.Reactant mixture cools down and is carefully added into water (10mL), is subsequently added AcOH (20mL).Continue to be stirred at room temperature 30min, and extraction in EtOAc (3 × 50mL).Organic layer is dried (Na2SO4), very Aerial concentration.By column chromatography (SiO2, 0-2%MeOH/DCM) and purification residue, obtain as yellow solid is titled Compound (1.1g, 13%).1H NMR(400MHz,CDCl3)δ7.70-7.60(m,3H),7.42(m,1H),5.94(bs,1H), 5.18(m,1H),2.70-2.40(m,3H),1.95(m,1H)。LCMS(ES+)230.0(M+H)+。
Intermediate 76
1-(the bromo-4-of 5-fluoro-2-nitrobenzophenone)-5-[2-(trifluoromethyl) phenyl] pyrrolidin-2-one
By the similar variant of method A, prepare title compound.To intermediate 75 (2.7g, 11.7mmol) in dry DMF (30mL) solution in adds cesium carbonate (9.57g, 29.4mmol) and 4-bromo-2,5-difluoro nitrobenzene (3g, 12.9mmol). Reactant mixture is stirred at room temperature 18h.By reactant mixture by add water (5mL) process, and with EtOAc (4 × 10mL) extraction.Organic layer water and saline are washed, is dried (Na2SO4), and concentrate in a vacuum.Pass through column chromatography (SiO2, 0-50%EtOAc/ hexane class) and purification residue, obtain the title compound (2.5g, 47%) as yellow solid. LCMS(ES+)447.0/449.0(M+H)+。
Intermediate 77
The fluoro-1-of the bromo-6-of 7-[2-(trifluoromethyl) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method B, prepare title compound from intermediate 76 (2.5g, 5.6mmol) and iron powder (941mg, 16.8mmol) Thing (2g, 89%).1H NMR(400MHz,CDCl3)δ7.80(m,1H),7.50(m,3H),6.90(d,1H),6.80(m,1H), 5.88(m,1H),3.30-3.15(m,3H),2.50(m,1H)。LCMS(ES+)399.0/401.0(M+H)+。
Intermediate 78 and 79
Enantiomer 1:(1R or S) the fluoro-1-of the bromo-6-of-7-[2-(trifluoromethyl) phenyl]-2,3-dihydro-1H-pyrrolo- [1,2-a] benzimidazole；Enantiomer 2 (1S or the R)-7-fluoro-1-of bromo-6-[2-(trifluoromethyl) phenyl]-2,3-dihydro- 1H-pyrrolo-[1,2-a] benzimidazole
By under the conditions of LC Chiralpak AD (100*500mm*mm, flow velocity 300mL/min, 30 DEG C, CO2+ MeOH 100%, the solution of the 65g/L concentration of injection 12.5mL) upper chirally purified 1.95g intermediate 77, separate title compound Thing.Collect the enantiomer 1 (RT 12min) of first eluting, and described fraction is evaporated to obtain 880mg intermediate 78.Receive Collect the enantiomer 2 (RT 21min) of the second eluting, and described fraction is evaporated to obtain 880mg intermediate 79.
Intermediate 80
7-bromo-1-(o-tolyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method B, prepare title compound from intermediate 18 (0.33g, 0.88mmol) and iron powder (0.24g, 4.4mmol) Thing (0.20g, 69%).1H NMR(400MHz,CDCl3)δ7.60(d,1H),7.30-7.25(m,3H),7.10(m,1H),7.00 (s,1H),6.80(d,1H),5.70(m,1H),3.15-3.05(m,3H),2.50(m,1H),2.45(s,3H)。LCMS(ES+) 327.0/329.0(M+H)+。
Intermediate 81
5-(2,5-3,5-dimethylphenyl)-5-oxo-pentanoate
To xylol (21mL, 170mmol) and the solution of 5-chloro-5-oxo-pentanoate (23.5mL, 170mmol) In, it is added portionwise into aluminum chloride (24.9g, 187mmol) lentamente.Reaction is heat release.After 1h, add xylol (40mL) To avoid the solidification of reactant mixture.Reactant is stirred at room temperature 2h.Add DCM (200mL), and the solution obtained is poured on Ice and saturated Na2CO3On aqueous solution.Aluminium salt is filtered, and by filtrate decant.Aqueous layer DCM is extracted, Organic substance is used 0.1M NaOH washs, and is dried (MgSO4) and concentrate in a vacuum.Residue (27.8g, 70%) is used without any purification.1H NMR(400MHz,CDCl3)δ7.43(m,1H),7.21(m,1H),7.07(m,1H),3.67(m,3H),2.95(m,2H), 2.46(m,5H),2.39(m,3H),2.06(m,2H)。GC-MS(CI)MH+235.18。
Intermediate 82
(5Z)-5-(2,5-3,5-dimethylphenyl)-5-oximido-methyl valerate
In the intermediate 81 (1.50g, 6.40mmol) solution in pyridine (5mL), addition oxammonium hydrochloride. (0.89g, 12.8mmol).Reactant mixture is heated in sealed tube 60 DEG C and keeps 20h.By reactant mixture cooling and in vacuum Middle concentration.By residue EtOH (2 × 10mL) dilution and concentrate in a vacuum, obtain title compound with quantitative yield (2.0g)。1H NMR(400MHz,CDCl3)δ8.42(m,1H),6.96(m,2H),3.66(m,3H),2.73(m,1H),2.48 (m,1H),2.38(m,2H),2.30(m,3H),2.21(m,3H),1.84(m,2H)。LC-MS:MH+250.3。
Intermediate 83
6-(2,5-3,5-dimethylphenyl) piperidines-2-ketone
Intermediate 82 (2.0g, 8.02mmol) is dissolved in EtOH (50mL), and is placed in autoclave.By Raney Ni (1.0g) add in mixture.Pour hydrogen (10 bar) to autoclave and heat 48h at 60 DEG C.By reactant mixture at kieselguhr Upper filtration also concentrates in a vacuum.Add DCM, organic layer is washed with water, is dried (MgSO4) and concentrate in a vacuum.Pass through Preparation HPLC purification residue, obtains 0.25g title compound (19%, 2 steps).1H NMR(400MHz,CDCl3)δ7.16 (m,1H),7.00(m,2H),6.04(m,1H),4.75(m,1H),2.47(m,2H),2.27(m,6H),2.09(m,1H),1.94 (m,1H),1.79(m,1H),1.59(m,1H)。LC-MS MH+204.2。
Intermediate 84
1-(5-bromo-2-nitro-phenyl)-6-(2,5-3,5-dimethylphenyl) piperidines-2-ketone
By method A, from intermediate 83 (0.25gr, 1.2mmol) and the bromo-2-of 4-fluoro-1-nitro-benzene (0.54g, 2.5mmol) prepare title compound.LCMS(ES+)403.2/405.2(M+H)+。
Intermediate 85
2-(2-(difluoro-methoxy) phenyl) oxirane
By 2-(difluoro-methoxy) benzaldehyde (110g, 639mmol), tetrabutylammonium iodide (2.360g, 6.39mmol) and The trimethyl sulfonium iodide (156g, 767mmol) mixture in DCM (900ml) and NaOH aqueous solution (50%, 600ml) is violent Stir 6 days.Reactant mixture DCM and water are diluted and separates each layer.Water layer DCM is extracted 3 times.Organic layer is merged, And wash with water and concentrate in a vacuum.Residue with diethyl ether is diluted, uses Na2S2O3Aqueous solution (1M, × 2), water (× 2) and Saline washing and dry (Na2SO4), obtain the title compound (135.8g, 96%) as yellow oil.1H NMR(300MHz, CDCl3-d)δ7.31(ddd,J 8.0,6.4,2.8Hz,1H),7.27-7.17(m,2H),7.13(d,J 8.0Hz,1H),6.56 (t,J 73.8Hz,1H),4.18(dd,J 4.1,2.6Hz,1H),3.17(dd,J 5.6,4.2Hz,1H),2.72(dd,J 5.7,2.6Hz,1H)。
Intermediate 86
(1-(2-(difluoro-methoxy) phenyl)-2-hydroxyethyl) t-butyl carbamate
By Hydrazoic acid,sodium salt (13.97g, 215mmol) and NH4Cl (11.49g, 215mmol) add intermediate 85 (40g, 215mmol) in the solution in the mixture of water (80ml) and MeOH (320ml).Flask is sealed, and reactant mixture is existed 50 DEG C of stirring 18h.After being cooled to room temperature, by reactant mixture argon cleaning, and add palladium (10 weight % in activated carbon, 2.287g,2.149mmol).The mixture obtained is stirred under a hydrogen atmosphere 5 hours, by purification for argon, over celite mistake Filter, and rinse with methanol.In filtrate, add Bis(tert-butoxycarbonyl)oxide (46.9g, 215mmol), and the mixture was stirred overnight. By mixture dilute with water, and MeOH is evaporated in vacuo.The precipitate formed is filtered, succeedingly washes with water, be dissolved in In EtOAc, it is dried (Na2SO4), and concentrate in a vacuum.Residue is ground together with ether, obtains as white solid Title compound (27.2g, 40%).1H NMR(300MHz,DMSO-d6)δ7.47-7.39(m,1H),7.34-7.20(m,3H), 7.19(t,J 74.0Hz,1Hz),7.12(dd,J 7.9,1.3Hz,1H),4.99-4.80(m,2H),3.53-3.34(m,2H), 1.45-1.10(m,9H)。LCMS(ES+)RT1.962min,248[M-tBuOCO+H]+。
Intermediate 87
2-amino-2-(2-(difluoro-methoxy) phenyl) ethylate hydrochlorate.
Intermediate 86 (84.7g, 279mmol) is dissolved in 1,4-bis-In alkane (the driest, 500ml), and add salt Acid is at 1,4-bis-Solution (4M, 880mmol, 220ml) in alkane.The mixture was stirred overnight.The precipitate mistake that will be formed Filter, washs with DCM, and is dried in a vacuum, obtain the title compound (55.8g, 79%) as white solid.1H NMR (300MHz,DMSO-d6)δ8.67(s,3H),7.73(dd,J 7.7,1.4Hz,1H),7.47(td,J 8.1,1.6Hz,1H), 7.39-7.22(m,2H),7.29(t,J 73.6Hz,1H),5.59(t,J 5.2Hz,1H),4.51(t,J 6.0Hz,1H), 3.78-3.62(m,2H)。LCMS(ES+):RT 2.33min,204[M-Cl]+。
Intermediate 88
(R)-5-(2-difluoro-methoxy-phenyl)-morpholine-3-ketone
To sodium hydride (dispersion in mineral oil of 6.67g, 167mmol, 60%, 4.0 equivalents) at THF (200mL) In suspension in add intermediate 87 (10g, 41.72mmol, 10g) and ethyl chloroacetate (1.2 equivalents, 50.07mmol, 6.14g).Reactant mixture is heated 14h at 75 DEG C, is then cooled to room temperature.Reactant mixture is dissolved in Et2In O, use water Wash 3 times with saline, be then dried (MgSO4) and concentrate in a vacuum.By residue iso-hexane, obtain as yellow The title compound (8.4g) of solid, it is further purified for next step without any.1H NMR(400MHz,CDCl3)δ: 7.41(d,J 7.7Hz,1H),7.29(m,1H),7.21(m,1H),7.06(m,1H),6.51(m,1H),5.05(m,1H), 4.02(m,1H),3.67(m,1H),3.59(dd,J 11.8Hz,J 6.3Hz,1H),3.40(q,J 7.0Hz,1H)。LCMS(ES+)244.0(M+H)+。
Intermediate 89
4-(the bromo-4-of 5-fluoro-2-nitro-phenyl)-5-(2-difluoro-methoxy-phenyl)-morpholine-3-ketone
By method A, with intermediate 88 (10.14g, 41.69mmol), DMF (35mL), sodium hydride (1.2 equivalents, 50.0mmol, 2.00g, the dispersion in mineral oil of 60%) and 4-bromo-2,5-difluoro nitrobenzene (1.0 equivalents, 41.69mmol, 9.92g) prepare title compound (5.62g, 29%).1H NMR(400MHz,CDCl3)δ:7.67(m,1H), 7.30(m,3H),7.00(m,2H),6.35(m,1H),4.37(m,4H),3.96(m,1H)。LCMS(ES+)461/463(M+H)+。
Intermediate 90
6-(2-(difluoro-methoxy) phenyl) piperazine-2-ketone
At 0 DEG C in the intermediate 26 (7.3g, 36.13mmol, 1 equivalent) solution in MeCN (30mL), add K2CO3 (4.98g, 36.13mmol, 1 equivalent) and ethyl chloroacetate (4.40g, 36.13mmol, 1 equivalent).By reactant mixture in room temperature Stirring 18h.Add water, and reactant mixture EtOAc is extracted.Organic layer water and saline are washed, is dried (Na2SO4) and Concentrate in a vacuum.By column chromatography (SiO2, 0-4%MeOH/DCM) and purification residue, obtain the mark as white solid Topic compound (3.2mg, 36%).1H NMR(400MHz,CDCl3)δ7.42(d,J 6.8Hz,1H),7.35-7.23(m,2H), 7.10(d,J 8Hz,1H),6.75-6.38(t,1H),5.01(m,1H),3.56(s,2H),3.30(d,J 17.6Hz,1H), 2.86(d,J 19.6Hz,1H)。LCMS(ES+)RT 1.29min,243.1(M+H)+。
Intermediate 91
3-(2-(difluoro-methoxy) phenyl)-5-oxypiperazin-1-t-butyl formate
At 0 DEG C in the intermediate 90 (3.2g, 13.22mmol, 1 equivalent) solution in anhydrous DCM (25mL), add three Ethamine (1.6g, 15.86mmol, 1.2 equivalent) and Bis(tert-butoxycarbonyl)oxide (3.45g, 15.86mmol, 1.2 equivalent).Will reaction Mixture is stirred at room temperature 6h.Add water and mixture DCM is extracted.Organic layer water and saline are washed, is dried (Na2SO4) and concentrate in a vacuum.By column chromatography (SiO2, 0-2%MeOH/DCM) and purification residue, obtain as white The title compound (3.2mg, 71%) of solid.1H NMR(400MHz,DMSO-d6)δ8.36(bs,1H),7.38(m,2H), 7.24(d,J 6.8Hz,1H),7.17(d,J 6.8Hz,1H),4.78(m,1H),4.42(d,J 17.6Hz,1H),3.84(d,J 12.4Hz,1H),3.77(d,J 18Hz,1H),3.63(d,J 11.2Hz,1H),1.10-1.29(s,9H)。LCMS(ES+)RT 2.19min,287.1(M+H-tBu)+。
Intermediate 92
4-(the bromo-4-of 5-fluoro-2-nitrobenzophenone)-3-(2-(difluoro-methoxy) the phenyl)-5-oxypiperazin tertiary fourth of-1-formic acid Ester
Title compound is prepared by the variant of method A.To intermediate 91 (5g, 14.61mmol, 1 equivalent) anhydrous In solution in MeCN (25mL), add K2CO3(6.05g, 43.5mmol, 3 equivalent) and 4-bromo-2,5-difluoro nitrobenzene (3.4g, 14.61mmol, 1 equivalent).Mixture is heated 20h at 90 DEG C in sealed tube.Reactant mixture is cooled down, adds Enter water, and mixture DCM is extracted.Organic layer water and saline are washed, is dried (Na2SO4) and concentrate in a vacuum.Logical Cross column chromatography (SiO2, 0-30%EtOAc/ hexane class) and purification residue, obtain the title compound as yellow solid (1.5g, 18%).1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.66(d,J 6.8Hz,1H),7.27-7.45(m, 5H),5.14(m,1H),4.56(d,J 16.4Hz,1H),4.03(d,J 15.2Hz,2H),3.18(d,J 16Hz,1H), 1.08-1.34(s,9H)。
Intermediate 93
4-(5-bromo-2-nitrobenzophenone)-3-(2-(difluoro-methoxy) phenyl)-5-oxypiperazin-1-t-butyl formate.
Title compound is prepared by the variant of method A.To intermediate 91 (2.92mmol, 1 equivalent) at anhydrous MeCN (15mL) solution in adds K2CO3(1.2g, 8.76mmol, 3 equivalent) and 4-bromo-2-fluoronitrobenzene (511mg, 3.21mmol, 1.1 equivalents).By mixture in sealed tube 90 DEG C of heating.After 26h, reactant mixture is cooled to room Temperature, adds water, and extracts with EtOAc, be dried (Na2SO4) and concentrate in a vacuum.By column chromatography (SiO2, 0-30% EtOAc/ hexane class) purification residue, obtain the title compound (225mg, 15%) as yellow solid.1H NMR (400MHz,DMSO-d6)δ8.05(d,J 8.4Hz,1H),7.93(s,1H),7.27-7.63(m,6H),5.43(m,1H), 4.29-4.38(m,3H),4.03(d,J 6.8Hz,1H),1.07-1.23(s,9H)。
Intermediate 94
2-[2-(difluoro-methoxy) phenyl]-2-morpholino-acetonitrile
2-(difluoro-methoxy) benzaldehyde (44g, 255.6mmol) is added dropwise over (keep temperature less than 25 DEG C) cold (0 DEG C) in morpholine (200g, 2.3moles).Add the KCN (20g, 307.1mmol, 1.2 equivalent) being dissolved in 25mL water, and will Reactant mixture stirs 2.5h at 80 DEG C.After cooling, the reactant mixture of solidification is dissolved in EtOAc (250mL), and will have Machine washs with water (250mL) mutually.Aqueous layer 150mL EtOAc is extracted 3 times.By organic layer use water (2 ×) merged, salt Water (1 ×) washs, and is dried (MgSO4) and concentrate in a vacuum, obtain the title compound (65g) as light slightly yellow oil, its It is further purified for next step without any.1H NMR(400MHz,DMSO-d6)δ:7.60(dd,J 7.6Hz,J 1.0Hz, 1H),7.45(m,1H),7.29(m,2H),6.50(dd,J 79.0Hz,J 70.2Hz,1H),3.68(m,5H),2.62(m, 4H)。
Intermediate 95
2-[2-(difluoro-methoxy) phenyl]-2-morpholino-pentane dintrile
The methanol solution (30%, 3mL) of KOH is added intermediate 94 (67g, 249.7mmol) stirring in 500mL THF Mix in solution.Then acrylonitrile (20g, 373.2mmol, 1.5 equivalent) is added in mixture, and by the solution that obtains in room temperature Stirring 3h.Mixture is concentrated in a vacuum, adds water (50mL), and mixture EtOAc is extracted.By extract water (150mL) washing, is dried (MgSO4) and concentrate in a vacuum, obtain the title compound (61g) as orange oil, its without Any it is further purified for next step.1H NMR(CDCl3)δ:7.68(dd,J 7.7Hz,J 1.1Hz,1H),7.47(td,J 7.9Hz,J 1.4Hz,1H),7.30(m,2H),6.54(dd,J 76.0Hz,J 71.3Hz,1H),3.74(t,J 4.5Hz, 4H),2.80(ddd,J 13.7Hz,J 10.5Hz,J 6.1Hz,1H),2.71(m,2H),2.55(ddd,J 13.8Hz,J 10.2Hz,J 5.3Hz,1H),2.47(m,2H),2.27(ddd,J 17.0Hz,J 10.3Hz,J 5.3Hz,1H),2.05 (ddd,J 17.1Hz,J 10.3Hz,J 6.0Hz,1H)。
Intermediate 96
4-[2-(difluoro-methoxy) phenyl]-4-oxo-butanenitrile
Intermediate 95 (82g, 255mmol) is dissolved in AcOH (300mL), water (150mL) and the mixing of THF (600mL) In thing, and 24h is stirred at room temperature.Then mixture is concentrated in a vacuum, orange residue is dissolved in EtOAc (800mL) In, with the NaOH solution washing of 1N until pH 8, with water, saline washing, it is dried (MgSO4) and concentrate in a vacuum, obtain Orange oil.By chromatography (SiO2, 0-20%EtOAc/ heptane) and purification, obtain the title compound as faint yellow oil (45g, 80%).1H NMR(400MHz,DMSO-d6)δ:7.83(dd,J 7.8Hz,J 1.4Hz,1H),7.57(m,1H),7.32 (m,1H),7.20(d,J 8.2Hz,1H),6.65(t,J 72.9Hz,1H),3.37(t,J 7.0Hz,2H),2.75(t,J 7.0Hz,2H)。
Intermediate 97
5-[2-(difluoro-methoxy) phenyl]-3,4-dihydro-2 h-pyrrole
Intermediate 96 (20g, 88.8mmol) is dissolved in 200mL EtOH.Add 12g Raney Ni and (wash 1 with EtOH Secondary), and the mixture obtained is hydrogenated 5.5h in room temperature at 1 bar.Filter by mixture argon-degassed and on bed of diatomaceous earth. Then light green color filtrate is concentrated in a vacuum, obtain as light green color oil title compound (18.5g, 98%), its without It is further purified for next step.1H NMR(400MHz,DMSO-d6)δ:7.82(m,1H),7.40(m,1H),7.20(m,2H), 6.55(m,1H),4.00(m,2H),2.98(m,2H),2.02(m,2H)。LCMS(ES+)RT 2.3min,212.0(M+H)+。
Intermediate 98
2-[2-(difluoro-methoxy) phenyl] pyrrolidine
Sodium borohydride (3.71g, 97.1mmol, 1 equivalent) is added portionwise into intermediate 97 (20.5g, 97.1mmol) exist In solution in 200mL MeOH.After reaction 1h, add another part sodium borohydride (1.85g, 0.5 equivalent, 48mmol), And the reactant mixture obtained is stirred at room temperature 5h.Add water in reactant mixture, and extract with EtOAc (3 ×).To close And organic layer use water (1 ×), then with saline (1 ×) wash, be dried (MgSO4), concentrate in a vacuum, obtain as shallow orange The title compound of color oil, it is further purified for next step (19.4g) without any.LCMS(ES+)RT 2.5min, 214.0(M+H)+。
Intermediate 99
1-(the bromo-4-of 5-fluoro-2-nitro-phenyl)-2-[2-(difluoro-methoxy) phenyl] pyrrolidine
By intermediate 98 (19.41g, 91.0mmol) add the bromo-2,5-of 1-bis-fluoro-4-nitro-benzene (21.66g, 91.0mmol, 1.0 equivalents) in solution in MeCN (180mL).It is subsequently adding K2CO3(15.25g, 109.2mmol, 1.2 work as Amount), and the reactant mixture obtained is stirred 14h at 80 DEG C.Reactant mixture is filtered, and solvent is concentrated in a vacuum, Obtain orange oil.This residue is dissolved in EtOAc, and washs with water (1 ×), be dried (MgSO4), concentrate in a vacuum, Obtaining the title compound (37g, 94%) as orange oil, it is further purified for next step without any.LCMS(ES+) RT 5.7min,431.0/433.0(M+H)+。
Intermediate 100
1-(5-bromo-2-nitro-phenyl)-2-phenyl-pyrrolidin
According to the method described about intermediate 99, from the bromo-2-of 2-Phenylpyrrolidine and 4-fluoro-1-nitro-benzene preparation mark Topic compound.LCMS(ES+)RT 5.68min,347.1/349.2(M+H)+。
Intermediate 101
(S)-N-[[2-(difluoro-methoxy) phenyl] methylene]-2-methyl-propan-2-sulfenamide
Addition (S) in 2-(difluoro-methoxy) benzaldehyde (4.7g, 0.027mol) solution in THF (3.44mL)- 2-methyl-2-propanesulfinamide (5.62g, 0.029mol).Add dipotassium hydrogen phosphate (potassium diphosphate Dibasic) (0.2 equivalent) and K3PO4(0.8 equivalent), and reactant mixture is stirred at room temperature 4h.Add DCM, reaction is mixed Compound washes with water, is dried (MgSO4) and concentrate in a vacuum, obtain the title compound (7g, 96%) as yellow oil, its Without further purification for next step.
Intermediate 102
(3R)-3-[[(S)-terf-butylsulfinyl] amino]-3-[2-(difluoro-methoxy) phenyl] ethyl propionate
Zinc powder (356.4g, 10 equivalents) and the copper chloride (53.95g, 1 equivalent) being dried of activation are returned in THF (1L) Stream heating 30min.Add the bromoacetate (227.5g, 2.5 equivalents) solution in THF (250mL), keep slight simultaneously And constant backflow.After being added completely into, mixture is heated at reflux 1h.At 0 DEG C, add intermediate 101 (150g, 1 equivalent) and exist Solution in THF (200mL), stirs reactant mixture 1h and filters over celite.Add water (300mL), solid precipitation Out, and add 1M HCl (1L) until precipitate be completely dissolved.By adding NaCl, by mixture decant.Organic facies is used Saline washing also concentrates in a vacuum.Residue is dissolved in DCM (1500mL), uses saturated NaHCO3Solution washing, dry Dry (MgSO4) and concentrate in a vacuum, obtain 3-(terf-butylsulfinyl amino)-3-[2-(difluoro-methoxy) phenyl] propanoic acid Ethyl ester (192g, 97%), is used for next step without further purification by it.
Intermediate 103
(3R)-3-amino-3-[2-(difluoro-methoxy) phenyl] ethyl propionate
To intermediate 102 (1.2g, 3.30mmol.) at Et2In solution in O (10mL), (4M is at Isosorbide-5-Nitrae-two to add HClSolution in alkane, 6.60mmol), and mixture is stirred at room temperature 10min.Add water in reactant mixture, and use Et2O extracts.By aqueous phase Na2CO3It is adjusted to alkaline pH, extracts with EtOAc, be dried (MgSO4) and concentrate in a vacuum, obtain 0.8g (90%) title compound.LCMS(ES+)2.83min,260(M+H)+.By with MosherShi reagent (R)-(+)-α-first Epoxide-α-trifluoromethylphenylacetic acid and (S)-(-)-α-methoxyl group-α-trifluoromethylphenylacetic acid derivatization, pass through subsequently NMR spectroscopy, it was demonstrated that the absolute configuration of (3R)-3-amino-3-[2-(difluoro-methoxy) phenyl] ethyl propionate.
Intermediate 104
(3R)-3-amino-3-[2-(difluoro-methoxy) phenyl] propane-1-alcohol
By LiBH4(1.9g, 2.2 equivalents) are suspended in THF (150mL), and by mixture 55-60 DEG C of heating.Dropwise Add the intermediate 103 (10.28g, 1 equivalent) solution in THF (40mL).Reactant mixture is stirred 1.5h at 65 DEG C, adds Enter the LiBH of additional quantity4(2 equivalent), and continue to heat 3h.Then reactant mixture is cooled to 0 DEG C and to add the HCl of 5N straight To pH 4.Mixture DCM is washed, and aqueous phase is adjusted to alkaline pH at 0 DEG C with 50%NaOH, with DCM:MeOH (8.5: 1.5) mixture extraction, is dried (MgSO4) and concentrate in a vacuum.The preparative reverse-phase chromatography purification instructed by UV is remaining Thing, obtains title compound (1.79g, 21%).LCMS(ES+)3.34min 218(M+H)+。
Intermediate 105
(3R)-3-(the bromo-4-of 5-fluoro-2-nitro-anilino)-3-[2-(difluoro-methoxy) phenyl] propane-1-alcohol
To molten in MeCN (200mL) of the bromo-2,5-of 1-bis-fluoro-4-nitro-benzene (10.41g), intermediate 104 (1 equivalent) Liquid adds K2CO3(2 equivalent).Reactant mixture is stirred 16h at 70 DEG C.Reactant mixture is concentrated in a vacuum, and by residual Excess is dissolved in (1:1) mixture of EtOAc/ water, and is adjusted to neutral pH with 1N HCl.Organic facies is dried (MgSO4) and Concentrate in a vacuum.By column chromatography (SiO2, 100%DCM) purification residue, obtain title compound (11.6g, 61%).
Intermediate 106
(3R)-3-(the bromo-4-of 5-fluoro-2-nitro-anilino)-3-[2-(difluoro-methoxy) phenyl] propionic aldehyde
Intermediate 105 (8.865g, 1.0 equivalents) is dissolved in DCM (400mL).Add TEMPO (0.01 equivalent), and Mixture is cooled to 0 DEG C, and adds the KBr (0.1 equivalent) solution in 1mL water, be subsequently added NaHCO3(0.4 equivalent) exists Solution in 8mL water.NaOCl (2 equivalent) is added dropwise in reactant mixture.Add 0.1N NaOH, by mixture DCM Extract 2 times, the organic facies 0.1N HCl merged and saline are washed, is dried (MgSO4) and concentrate in a vacuum, obtain title Compound (8.57g, 97%).
Intermediate 107
(4R)-4-(the bromo-4-of 5-fluoro-2-nitro-anilino)-4-[2-(difluoro-methoxy) phenyl]-2-trimethyl first silicon Alkyl oxy-butyronitrile
Intermediate 106 (35,92g, 1.0 equivalents) and triethylamine (0.1 equivalent) are dissolved in DCM (500mL).Add three Methyl silicane base cyanide (1.2 equivalent), and reactant mixture is stirred at room temperature 6h.Add water, mixture DCM is extracted Take 2 times, by organic phases washed with brine, be dried (MgSO4) and concentrate in a vacuum, obtain the title compound as oil (40.05g, 91%).
Intermediate 108
Diastereomer 1:(1R, 3S or R) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro- 1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
Intermediate 107 (40.5g, 1.0 equivalents) and iron powder (3 equivalent) are dissolved in AcOH (70mL), and reaction is mixed Compound stirs 1h at 100 DEG C.In room temperature, add water, mixture DCM is extracted, the saturated NaHCO of organic facies that will merge3 Solution washing, dry (MgSO4) and concentrate in a vacuum.SFC condition is used to pass through chiral chromatography on Lux-Cell-4 (50*261mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%MeOH, the solution of the 30g/L concentration of injection 3.66mL) pure Change residue.Collect the diastereomer (RT 5.15min) of first eluting, and described fraction evaporated to obtain 1R, 3R or S diastereomer (550mg, 64.4%).Collect the diastereomer (RT 7.95min) of the second eluting, and by described level Divide evaporation to obtain title compound (90mg, 10.5%).LCMS(ES+)RT 4.49min,413.0/415.0(M+H)+。
Intermediate 109
The bromo-1-of 7-[2-(difluoro-methoxy) phenyl]-6-fluoro-3-methyl isophthalic acid, 2-glyoxalidine also [1,2-a] benzimidazole
Intermediate 31 (13mg, 0.033mmol) is dissolved in 500 μ L DMF.At 0 DEG C, addition sodium hydride (4mg, 0.100mmol, 60 mass %).Continue reaction 2h, be subsequently adding iodomethane (10 μ L, 0.161mmol).Continue at room temperature reaction 2h, is subsequently adding water (2mL) and EtOAc (2mL).Organic layer saline (2mL) is washed, through MgSO4Be dried and in a vacuum Concentrate.By chromatography (SiO2, the EtOAc of 50-100% solution in heptane) and purification residue, obtain title compound (6mg, 44%).LCMS(ES+)RT 4.96min,412.0/414.0(M+H)+。
Intermediate 110
(1R) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-8-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzo miaow Azoles-3-alcohol
K is added in the intermediate 103 (5g, 16.8mmol) solution in anhydrous MeCN (40mL)2CO3(6.9g, 50mmol) with 4-bromo-2,3-difluoro nitrobenzene (4.8g, 20.2mmol).Reactant mixture is stirred 18h at 80 DEG C.Will reaction Mixture use water (100mL) dilutes, and extracts with EtOAc (2 × 150mL).By organic layer use water (300mL) merged, saline (250mL) washing, through Na2SO4It is dried and concentrates in a vacuum.By chromatography (SiO2, molten in heptane of the EtOAc of 10% Liquid) purification residue, obtain yellow solid (6.2g, 77%).
In the intermediate (6.2g, 13.02mmol) solution in THF (60mL), it is added dropwise over DIBAL-H at-78 DEG C (23mL,23.5mmol).Reactant mixture is stirred 2h at-78 DEG C.After reaction terminates (being monitored by TLC), reaction is mixed Compound aqueous ammonium chloride solution (200mL) quencher.Reactant mixture EtOAc (200mL) is diluted and passes kieselguhr and filter. By filtrate water (200mL) washing and organic layer is separated, through Na2SO4Being dried and concentrate in a vacuum, (57% receives to obtain 3g Rate) yellow oil, it is without further purification for next step.
The solution in DCM (50mL) of the intermediate (3g, 6.42mmol) forwardly adds ZnI2(0.2g, 0.64mmol), TEA (0.09mL, 0.64mmol) and TMSCN (1.6mL, 12.84mmol).Reactant mixture is stirred at room temperature 3h.After reaction terminates (being monitored by TLC), by reactant mixture use water (100mL) dilution and organic layer is separated.By organic The washing of layer use water (100mL), saline (100mL), through Na2SO4It is dried and concentrates in a vacuum, obtaining 3.25g crude material, its Without further purification for next step.
The solution in EtOH (50mL) of the intermediate (3g, 5.3mmol) forwardly adds SnCl2(5g, 26.46mmol), and by reactant mixture 2h is heated at 80 DEG C.After reaction terminates (being monitored by TLC), by reactant mixture With water (50mL) quencher, and use 1N KOH (100mL) alkalization to pH-8.Reactant mixture EtOAc (100mL) is diluted also Filter through kieselguhr.By organic layer use water (100mL), saline (100mL) washing, through Na2SO4It is dried and concentrates in a vacuum. By chromatography (SiO2, the EtOAc of 0-70% solution in hexane) and purification residue, obtain the mark as Light brown solid Topic compound (0.85g, 36%).LCMS(ES+)RT 2.42min,413.0/415.1(M+H)+。
Intermediate 111 and 112
The bromo-1-of (1R, 3R)-7-[2-(difluoro-methoxy) phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles and the bromo-1-of (1R, 3S)-7-[2-(difluoro-methoxy) phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles
According to about prepare intermediate 110 describe operation, but in the first step use the bromo-2-of 4-fluoro-1-nitro-benzene As reagent, the preparation bromo-1-of (1R)-7-[2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzo miaow Azoles-3-alcohol.
At 0 DEG C to the bromo-1-of compound (1R)-7-[2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole-3-alcohol (100mg, 0.25mmol) solution in DCM (5mL) adds DAST (0.04mL, 0.32mmol). By reactant mixture at mutually synthermal stirring 30min.After reaction terminates (being monitored by TLC), by reactant mixture with saturated NaHCO3Solution quencher, and extract with DCM, through Na2SO4It is dried and concentrates in a vacuum.By chromatography (SiO2, 0-20%'s EtOAc solution in hexane) purification residue, obtain brown oil (30mg, 30%).LCMS(ES+)397(M+H)+。
By under the conditions of SFC Chiralpak AD (50*216mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 30%i-PrOH, the solution of the 45g/L concentration of injection 11mL) upper chirally purified, by chirally purified above intermediate, marked Topic intermediate.Collect the diastereomer (RT 6.00min) of first eluting, and by titled to obtain for the evaporation of described fraction Compound, intermediate 111 (150mg, 33%).Collect the diastereomer (RT 9.77min) of the second eluting, and by described level Divide evaporation to obtain intermediate 112 (240mg, 53%).
Advances in crystal X-ray diffraction allows to determine the absolute configuration of two chiral centres.
Intermediate 113
4-(5-Bromopyrimidine-2-base) Pentamethylene oxide .-4-alcohol
The iodo-pyrimidine of bromo-for 5-2-(20.02g, 70.28mmol) is dissolved in dry toluene (12.5mL).At-78 DEG C, add Enter the n-BuLi of 2.7mol/L solution (28mL, 76mmol) in hexane, be subsequently added tetrahydrochysene-4H-pyrans-4-ketone (7.39g, 73.81mmol) solution in dry toluene (3.5mL).Reactant mixture is stirred 1h at-78 DEG C.At 0 DEG C, will Reactant mixture, by adding water (200mL) quencher, extracts with 3 × 100mL EtOAc.The organic layer water that will merge (100mL), saturated brine solution (2 × 100mL) washing, dried over sodium sulfate and concentrate in a vacuum.Pass through chromatography (SiO2, the EtOAc of 7-25% solution in heptane) and purification residue, obtain the title compound as yellow solid (5.2g, 18%).LCMS alkali (ES+)241.27(M+H)+。
Intermediate 114
The bromo-2-of 5-(4-fluorine tetrahydropyran-4-base) pyrimidine
Under an argon atmosphere, intermediate 113 (0.15g, 0.58mmol) is dissolved in dichloromethane (10mL).At 0 DEG C, Add diethylaminosulfur trifluoride (0.093g, 0.58mmol), and mixture is stirred 30 minutes at 0 DEG C.Reaction is mixed Thing carries out quencher by adding water, extracts with DCM (3 × 20mL).By dried over sodium sulfate and in a vacuum for the organic layer that merges Concentrate.By chromatography (SiO2, the EtOAc of 10-20% solution in heptane) and purification residue, obtain as white solid Title compound (83mg, 56%).LCMS acid (ES+)261.00(M+H)+
Intermediate 115
2-chloro-6-(difluoro-methoxy) benzaldehyde
In the 2-chloro-6-hydroxy-benzaldehyde (20g, 128.2mmol) solution in MeCN (150mL), hydrogen is added at 0 DEG C The potassium oxide (71.7g, 1282mmol) aqueous solution in water (50mL), and reactant mixture is stirred 10 minutes at 0 DEG C.0 DEG C add (bromine difluoro methyl) diethyl phosphonate (36.4mL, 205.1mmol).Reactant mixture is stirred 30 minutes at 0 DEG C.Instead After should terminating (being monitored by TLC), reactant mixture is poured in water (500mL).Aqueous layer with ethyl acetate (1L × 2) is extracted Take.By organic layer use water (500mL), saline (500mL) washing, and it is dried through anhydrous sodium sulfate.Organic layer is under reduced pressure steamed Send out and obtain crude product, passed through column chromatography (SiO2, the EtOAc of 5% solution in hexane) and purification, obtain as yellow The title compound (13.9g, 53%) of oil.1H NMR(400MHz,CDCl3)δ10.46(s,1H),7.49(t,J 8.2Hz, 1H),7.37(dd,J 8.1,1.1Hz,1H),7.20(m,1H),6.61(t,1H)。
Intermediate 116
N-[[2-chloro-6-(difluoro-methoxy) phenyl] methylene]-(S)-2-methyl-propan-2-sulfenamide
0 DEG C add in the intermediate 115 (20g, 97.08mmol) solution in anhydrous THF (100mL) (S)-(-)- T-butyl sulfonamide (12.92g, 106.79mmol), K3PO4(61.73g, 291.2mmol) and K2HPO4(50.6g, 291.2mmol).Then reactant mixture is stirred at room temperature 18h.After reaction terminates (being monitored by TLC), reaction is mixed Thing filters through kieselguhr, and washs by ethyl acetate (1L).By organic layer use water (500mL), saline (500mL) washing, and It is dried through anhydrous sodium sulfate.Organic layer is under reduced pressure evaporated, and by residue by chromatography (SiO2, the EtOAc of 10% exists Solution in hexane) purification, obtain the title compound (20g, 87%) as yellow oil.1H NMR(400MHz,CDCl3)δ 8.90(s,1H),7.45-7.32(m,2H),7.29-7.15(m,1H),6.82-6.34(m,1H),1.29(s,9H)。LCMS(ES +)RT 2.73min,309.90(M+H)+
Intermediate 117
(3R)-3-[[(S)-terf-butylsulfinyl] amino]-3-[2-chloro-6-(difluoro-methoxy) phenyl] ethyl propionate
This zinc operating with activation and the THF being dried through sodium and benzophenone complex.Operations described below preparation is used to live The zinc changed: put into by 150g zinc powder in 1N HCl (500mL), stirs 10 minutes and decant.By zinc powder powder use water (3 × 500mL) wash also decant further.Being washed further by powder acetone (3 × 500mL), decant is also dried under vacuum, Zinc to 105g activation.
Add in the zinc powder (105g, 1618mmol) of the activation in anhydrous THF (150mL) CuCl (19.2g, 194mmol), and by reactant mixture reflux 30 minutes.Reactant mixture is cooled to room temperature, and is added dropwise over bromoacetate (45mL,404mmol in THF 100mL).Reactant mixture is stirred 30min at 50 DEG C.Reactant mixture is cooled to 0 DEG C, and add intermediate 116 (50g, 161mmol are in THF 100mL).Reactant mixture is warmed to room temperature and stirs 3h.Instead After should terminating (being monitored by TLC), reactant mixture is filtered through kieselguhr, and wash by ethyl acetate (700mL).Will Organic layer 1N citric acid (500mL), saturated sodium bicarbonate solution (500mL), water (500mL) and saline (500mL) washing.Will Organic layer separates, and is dried through anhydrous sodium sulfate and under reduced pressure evaporates.By chromatography (SiO2, the EtOAc of 40% is in hexane Solution) purification residue, obtain the title compound (59g, 92%) as yellow oil.1H NMR(400MHz,CDCl3)δ 7.29-7.21(m,2H),7.05(d,J 7.3Hz,1H),6.82-6.34(m,1H),5.59(m,1H),4.36(s,1H), 4.18-4.02(m,2H),3.25(dd,J 15.6,7.5Hz,1H),3.01(dd,J 15.3,7.5Hz,1H),1.31-1.11 (m,12H)。
Intermediate 118
(3R)-3-amino-3-[2-chloro-6-(difluoro-methoxy) phenyl] propionate hydrochloride
To intermediate 117 (32g, 80.6mmol) at ether: the solution in EtOH (75mL, 2:1) mixture adds 4M HCl at 1,4-bis-Solution (70mL) in alkane, and reactant mixture is stirred at room temperature 1h.Reaction terminates (to pass through TLC Monitoring) after, reactant mixture is under reduced pressure concentrated, and residue with diethyl ether (500mL) is washed, obtain as yellow solid The title compound (22g, 93%) of body.1H NMR(400MHz,CDCl3)δ8.93(d,J 6.2Hz,2H),7.32-7.10(m, 3H),6.96(s,1H),5.42(m,1H),4.08(q,J 7.0Hz,2H),3.36(dd,J 16.5,7.0Hz,1H),3.14 (dd,J 16.5,7.8Hz,1H),1.34(t,J 7.1Hz,3H)。
Intermediate 119
(3R)-3-(the bromo-4-of 5-fluoro-2-nitro-anilino)-3-[2-chloro-6-(difluoro-methoxy) phenyl] ethyl propionate
In the intermediate 118 (5g, 17.06mmol) solution in MeCN (50mL) add potassium carbonate (7.06g, 51.18mmol) with the fluoro-4-Nitrobenzol of the bromo-2,5-of 1-bis-(4.86g, 20.47mmol).By reactant mixture 80 DEG C of stirrings 16h.After reaction terminates (being monitored by TLC), reactant mixture ethyl acetate (100mL) is diluted, and with water (100mL) Washing.Organic layer is separated, is dried through anhydrous sodium sulfate and under reduced pressure concentrates.By chromatography (SiO2, the EtOAc of 20% Solution in hexane) purification residue, obtain the title compound (6g, 69%) as yellow viscous liquid.
LCMS(ES+)RT 3.42min,510.90/512.90/514.90(M+H)+
Intermediate 120
(3R)-3-(the bromo-4-of 5-fluoro-2-nitro-anilino)-3-[2-chloro-6-(difluoro-methoxy) phenyl] propionic aldehyde
In the intermediate 119 (6g, 11.7mmol) solution in THF (60mL), it is added dropwise over DIBAL-H at-78 DEG C (23mL,23.5mmol).Reactant mixture is stirred 2h at-78 DEG C.After reaction terminates (being monitored by TLC), reaction is mixed Compound aqueous ammonium chloride solution (200mL) quencher.Reactant mixture ethyl acetate (200mL) is diluted and passes kieselguhr mistake Filter.By filtrate water (200mL) washing and organic layer is separated, dried over sodium sulfate and under reduced pressure evaporate, obtain as Huang The title compound (3g, 57%) of color oil, it is without further purification for next step.
Intermediate 121
(4R)-4-(the bromo-4-of 5-fluoro-2-nitro-anilino)-4-[2-chloro-6-(difluoro-methoxy) phenyl]-2-trimethyl Silicyl epoxide-butyronitrile
ZnI is added in the intermediate 120 (3g, 6.42mmol) solution in DCM (50mL)2(0.2g,0.64mmol)、 TEA (0.09mL, 0.64mmol) and TMSCN (1.6mL, 12.84mmol).Reactant mixture is stirred at room temperature 3h.Reaction knot After bundle (being monitored by TLC), by reactant mixture use water (100mL) dilution and organic layer is separated.By organic layer water (100mL), saline (100mL) washing, be dried through anhydrous sodium sulfate and under reduced pressure concentrate, (3.25g is thick to obtain title compound Material processed), it is used for next step without further purification.
Intermediate 122
(1R) the bromo-1-of-7-[2-chloro-6-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] Benzimidazole-3-alcohol
SnCl is added in the intermediate 121 (3g, 5.3mmol) solution in EtOH (50mL)2(5g, 26.46mmol), And reactant mixture is heated 2h at 80 DEG C.After reaction terminates (being monitored by TLC), by sudden for reactant mixture water (50mL) Go out, and use 1N KOH (100mL) to alkalize to pH-8.Reactant mixture ethyl acetate (100mL) is diluted and passes diatom Soil filters.By organic layer use water (100mL), saline (100mL) washing, it is dried through anhydrous sodium sulfate and under reduced pressure concentrates.Logical Cross chromatography (SiO2, the EtOAc of 0-70% solution in hexane) and purification residue, obtain the title as Light brown solid Compound (1.1g, 47% yield).1H NMR(400MHz,CDCl3)δ7.52(m,1H),7.49-7.30(m,2H),7.04- 6.67(m,2H),6.42(m,1H),6.24-5.91(m,1H),5.79-5.52(m,1H),3.71-3.46(m,1H),3.19(m, 2H)。LCMS(ES+)RT 2.39min,447.0/449.0/451.0(M+H)+
Intermediate 123 and 124
The bromo-1-of (1R, 3R)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole-3-alcohol and the bromo-1-of (1R, 3S)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrole Cough up also [1,2-a] benzimidazole-3-alcohol
By under the conditions of SFC Chirapak AD (post size: 50*216mm*mm, flow velocity 360mL/min, 300mg/ injection/frequency: 8.5 minutes, 25 DEG C, CO2+ 20%MeOH) upper chirally purified intermediate 122 (15g), separate titled Compound.At Chiralpak AD-H, (flow velocity 1mL/min, at 30 DEG C, uses containing 0.1% for post size: 250*4.6mm, 5 μm 80/20 heptane of DEA/ethyl acetate) on carry out chiral analysis.Under analysis condition, the first diastereomer of eluting (5.8 and 9.5 minutes) are (1R, 3S) and (1R, 3R) bromo-1-of-7-[2-chloro-6-(difluoro-methoxy) phenyl] the fluoro-2,3-of-6-bis- The mixture of hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol.
(1S, 3R) and (1S, 3S) bromo-1-of-7-[the chloro-6-of 2-(difluoro-methoxy) is separated at 12.5 minutes and 21.5 minutes Phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol.
By under the conditions of SFC at Chiracel OD (post size: 50*266mm*mm, flow velocity 360mL/min, 80mg/ Injection/frequency: 4 minutes, 25 DEG C, CO2+ 20%MeOH) upper chiral separation, separate (1R, 3S) and (1R, 3R)-7-bromo-1-[2- Chloro-6-(difluoro-methoxy) phenyl] mixture of-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol.? (flow velocity 1mL/min, at 30 DEG C, uses 70/ containing 0.1%DEA to Chiralpak AD-H for post size: 250*4.6mm, 5 μm 30 heptane/ethyl acetate) on carry out chiral analysis.Under analysis condition, the first diastereomer (4.9 minutes) of eluting is Transisomer, the bromo-1-of (1R, 3S)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo- [1,2-a] benzimidazole-3-alcohol.The fraction evaporation that will merge, obtains intermediate 124 (12.7g, 50%).1H NMR (400MHz,CDCl3)δ7.41(m,3H),7.23(d,J 8.0Hz,0.4H),6.97(m,1.2H),6.85(d,J 5.8Hz, 0.4H),6.73(t,J 72.3Hz,0.4H),6.41(m,1H),5.95(dd,J 74.2,70.8Hz,0.6H),5.71(m, 0.6H),5.62(d,J 7.4Hz,0.4H),3.22(m,2H).Mixture as rotamer 6/4.LCMS alkali (ES+) 2.50min.,446.96/448.95/450.95(M+H)+。
Under analysis condition, the diastereomer (6.6 minutes) of the second eluting is cis-isomer, (1R, 3R)-7- Bromo-1-[2-chloro-6-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol.Will The fraction evaporation merged, obtains intermediate 123 (6.6g, 26%).1H NMR(400MHz,CDCl3)δ7.45(d,J 8.5Hz, 1H),7.31(m,1.8H),7.20(m,0.6H),7.08(d,J 7.9Hz,0.6H),6.88(d,J 5.5Hz,0.6H),6.74 (d,J 5.2Hz,0.4H),6.61(t,J 72.5Hz,0.4H),6.15(t,J 72.0Hz,0.6H),6.08(m,1H),5.63 (m, 1H), 3.56 (m, 0.6H), 3.43 (m, 0.4H), 2.98 (m, 0.4H), 2.80 (m, 0.6H), as rotamer 6/4 Mixture.LCMS acid (ES+)2.20min,446.96/448.95/450.91(M+H)+。
Under preparation condition, eluting is out of order.
Intermediate 125
The bromo-1-of (1R, 3S)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole-3-alcohol
Prepare title compound also by operations described below: under inert nitrogen atmosphere by intermediate 123 (3.65g, 8.146mmol, 1 equivalent) and triphenylphosphine (2.62g, 9.775mmol, 1.2 equivalent) be dissolved in the anhydrous THF of 8mL.Add second Acid (513 μ L, 8.960mmol, 1.1 equivalent), and mixture is cooled to 0 DEG C.Be added dropwise over DIAD (2.42mL, 12.220mmol, 1.5 equivalents) solution in the anhydrous THF of 8mL.Reactant is warmed to room temperature lentamente, and continues in this temperature Continuous reaction 2 hours.20mL ethyl acetate is added in reactant mixture, then with the saturated NaHCO of 3 × 10mL3Solution washs. Organic layer is dried through anhydrous magnesium sulfate and is concentrated under vacuum.By chromatography (SiO2, molten in DCM of the MeOH of 5% Liquid) purification residue, obtain the Acetate Intermediate that 4.8g (94% yield) inverts, be used directly in next step.Will [the bromo-1-of (1R, 3S)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzo Imidazo-3-yl] acetas (4.8g, 9.800mmol, 1 equivalent) is dissolved in 48mL methanol.Addition potassium carbonate (1.4g, 9.800mmol, 1 equivalent), and continue, room temperature reaction 1 hour, to be evaporated by reactant, and residue is dissolved in ethyl acetate (50mL) and water (20mL) in.Organic layer use water (2 × 20mL) is washed, dried over sodium sulfate, filter and be concentrated under vacuum, Obtain the 4.7g crude title compound as pale beige solid.
Intermediate 126
(3R)-3-(5-bromo-2-nitro-anilino)-3-[2-chloro-6-(difluoro-methoxy) phenyl] ethyl propionate
Use the same operation that the preparation about intermediate 119 describes, from intermediate 118 (9.3g, 28.3mmol) and 4- The fluoro-Nitrobenzol of bromo-2-(7.4g, 34mmol) prepares intermediate 126.Reactant is stirred overnight at 80 DEG C and passes through chromatography (SiO2, the EtOAc of 10% solution in hexane) and purification.Obtain the intermediate 126 (12.5g, 90%) as yellow oil.
LCMS(ES+)493.0/495.0(M+H)+
Intermediate 127
(3R)-3-(5-bromo-2-nitro-anilino)-3-[2-chloro-6-(difluoro-methoxy) phenyl] propionic aldehyde
Use the same operation that the preparation about intermediate 120 describes, prepare from intermediate 126 (12.5g, 25.4mmol) Intermediate 127.After post processing, by chromatography (SiO2, the EtOAc of 15% solution in hexane) and in purification of crude Mesosome 127, obtains the intermediate 127 (9g, 80%) as yellow oil.1H NMR(400MHz,CDCl3)δ9.80(d,J 1.3Hz,1H),8.78(d,J 9.0Hz,1H),7.99(d,J 9.0Hz,1H),7.27(d,J 3.2Hz,2H),7.21-7.08 (m,1H),6.81-6.66(m,2H),5.93(m,1H),3.56-3.38(m,2H),3.12(dd,J 17.9,5.2Hz,1H)。
Intermediate 128
(4R)-4-(5-bromo-2-nitro-anilino)-4-[2-chloro-6-(difluoro-methoxy) phenyl]-2-trimethyl first silicon Alkyl oxy-butyronitrile
Use the same operation that the preparation about intermediate 121 describes, in the middle of intermediate 127 (9g, 20mmol) preparation Body 128.Reactant is stirred at room temperature 2h.After reaction terminates (being monitored by TLC), add water (200mL), and use DCM (500mL) extraction.After evaporation organic layer, the crude product (9g) obtained as yellow oil is directly used in down without any purification One step.
Intermediate 129
(1R) the bromo-1-of-7-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzo miaow Azoles-3-alcohol
Use the same operation that the preparation about intermediate 122 describes, from prepared by intermediate 128 (9g, 16.4mmol) Mesosome 129.By crude product by chromatography (SiO2, the EtOAc of 60% solution in hexane) and purification, then with hexane: second Acetoacetic ester grinds together, obtains the title compound (3g, 43% yield) as yellow solid.LCMS(ES+)429.0/431.0 (M+H)+
Intermediate 130 and 131
The bromo-1-of (1R, 3R)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles-3-alcohol and the bromo-1-of (1R, 3S)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole-3-alcohol
By 2 continuous chiral separation, separate title compound by chirally purified intermediate 129 (12.5g).
Chiral separation for the first time:
Under the conditions of SFC, at Chiracel OD, (post size: 50*266mm*mm, flow velocity 360mL/min, 20mg/ note Penetrate/frequency: 4 minutes, 25 DEG C, CO2+ 20%MeOH) on.At Chiralcel OD-H (post size: 250*4.6mm, flow velocity 1mL/min, at 30 DEG C, uses containing 100% methanol of 0.1%DEA) on carry out chiral analysis.Under analysis condition, first wash De-diastereomer (3.9 minutes) be (1S, 3R) or (1S, 3S) bromo-1-of 7-[2-chloro-6-(difluoro-methoxy) phenyl]- 2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol.The diastereomer (4.7 minutes) of the second eluting be (1R, 3S) and (1S, 3R) or (1S, 3S) bromo-1-of-7-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo- The mixture of [1,2-a] benzimidazole-3-alcohol, and the diastereomer (5.4 minutes) of the 3rd eluting is that (1R, 3R)-7-is bromo- 1-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol.The will merged The fraction evaporation of the diastereomer of three eluting, obtains intermediate 130 (3.63g, 29%).1H NMR(400MHz,DMSO)δ 7.57(m,2.3H),7.45(m,0.8H),7.35(d,J 8.0Hz,0.6H),7.26(m,1H),7.17(m,0.3H),6.83 (t,J 72.5Hz,1H),6.69(bs,1H),6.15(m,1H),6.07(m,1H),5.38(m,1H),3.38(m,1H),2.67 (m, 1H), as the mixture of rotamer 7/3.LCMS acid (ES+)RT4.31min.,429.10/431.08/433.05(M +H)+。
Chiral separation for the second time:
At Whelko 01 (R, R) (post size: 50*227mm*mm, flow velocity 360mL/min, 690mg/ under the conditions of SFC Injection/frequency: 5.5 minutes, 25 DEG C, CO2+ 20%EtOH) on.At Chiralcel OD-H (post size: 250*4.6mm, stream 1mL/min is at 30 DEG C for speed, uses containing the 50/50 heptane/isopropanol of 0.1%DEA) on carry out chiral analysis.
Under analysis condition, the first diastereomer (4.1 minutes) of eluting is that (1S, 3R) or (1S, 3S)-7-is bromo- 1-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol.
Under analysis condition, the diastereomer (5.9 minutes) of the second eluting is transisomer, (1R, 3S)-7- Bromo-1-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol.To merge Fraction evaporation, obtain intermediate 131 (4.46g, 36%).1H NMR(400MHz,DMSO)δ7.55(m,3.4H),7.31(m, 1.4H),7.12(d,J 7.8Hz,0.6H),7.03(t,J 73.0Hz,0.6H),6.89(s,0.6H),6.81(s,0.4H), 6.32(dd,J 8.4,5.9Hz,1H),6.10(d,J 6.6Hz,1H),5.32(m,0.6H),5.26(t,J 6.9Hz,0.4H), 3.13(m,1H),2.93(m,1H).Mixture as rotamer 6/4.LCMS acid (ES+)RT 4.40min., 429.05/431.08/433.05(M+H)+。
Under preparation condition, eluting is out of order.
Intermediate 132
The bromo-1-of (1R, 3S)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles-3-alcohol
Use about intermediate 125 preparation describe same operation, from intermediate 130 (3.63g, 8.450mmol), three Phenylphosphine (2,66g, 10.14mmol) and acetic acid (0.5mL, 9.295mmol), THF (34mL), DIAD (2.62mL, 12.67mmol) solution in the anhydrous THF of 5ml starts, and prepares title compound, obtains the acetas that 3.6g (91%) inverts Intermediate, is directly used in next step.Use following condition.
By [the bromo-1-of (1R, 3S)-7-[2-chloro-6-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2a] Benzimidazole-3-base] acetas (4.0g, 8.480mmol) is dissolved in 40mL methanol.Addition potassium carbonate (1.1g, 8.48mmol, 1 equivalent), and continue room temperature reaction 1 hour.Methanol is evaporated, and residue is dissolved in ethyl acetate (50mL) and water (20mL) in.By organic layer use water (2 × 20mL) wash, be dried through anhydrous sodium sulfate, filter and under vacuo Concentrate, obtain the 4.9g crude title compound as brown oil, it is used without further purification.LCMS(ES+)RT 2.46min.,428.94/430.96/433.16(M+H)+。
Intermediate 133
3-(5-Bromopyrimidine-2-base) oxetanes-3-alcohol
The iodo-pyrimidine of bromo-for 5-2-(20.02g, 70.28mmol) is dissolved in dry toluene (260mL).At-78 DEG C, by It is added dropwise to the n-BuLi of 1.6mol/L solution (44mL, 70.0mmol) in hexane, and is added dropwise over oxa-ring fourth subsequently The alkane-3-ketone (4.5mL, 73.3mmol) solution in anhydrous dry toluene (40mL).By reactant mixture-78 DEG C of stirrings 1h.At 0 DEG C, reactant mixture is carried out quencher by adding distilled water (500mL), extracts by 4 × 200mL ethyl acetate.Will The ascorbic acid solution of organic layer 2.5M, the saturated NaCl solution (200mL) that merge are washed, dried over sodium sulfate, and very It is concentrated to give crude product in the air, it is filtered over celite.By kieselguhr DCM, the washing of hot Di Iso Propyl Ether, and will merge Filtrate concentrate in a vacuum.The thick residue obtained is crystallized in the mixture of isopropyl ether and toluene, obtains as Huang The title compound (1.8g, 11%) of color solid.LCMS(ES+)231.03(M+H)+。
Intermediate 134
[3-(5-Bromopyrimidine-2-base) oxetanes-3-base] epoxide-trimethyl-silane
Intermediate 133 (2.7g, 12.85mmol) and imidazoles (0.95g, 13.9mmol) are mixed in DCM (9mL/mmol) Close.Add trimethylsilyl chloride (1.52mL, 16.71,1.3 equivalents), and reactant mixture is stirred at room temperature 1.5h.Add Trimethylsilyl chloride (1mL), and continue to stir 3h.It is subsequently adding imidazoles (0.450mg), and reactant mixture is stirred additionally 1.5h.Reactant mixture is filtered, residue DCM (3 × 100mL) is washed.By filtrate with distilled water (2 × 100mL), satisfy Wash with NaCl solution (100mL), dried over magnesium sulfate, and concentrate in a vacuum, obtain the title compound as yellow oil (3.7g, 96%).LCMS(ES+)303.17(M+H)+。
Intermediate 135
The bromo-2-of 5-(3-fluorine oxetanes-3-base) pyrimidine
Intermediate 134 (3.53g, 12.1mmol) is dissolved in DCM (4.2mL).At-78 DEG C, it is added dropwise over DAST (1.81mL,14.2mmol).Reactant mixture is stirred 0.5h at-78 DEG C, 1h is then stirred at room temperature.Add DAST (0.5mL, 14.2mmol), and stir the mixture for other 3h.It is subsequently adding DAST (1.0mL, 7.82mmol), and by mixture 1h is stirred at room temperature again.Add saturated NaHCO3Solution, and after decant, organic layer is dried over magnesium sulfate, and in a vacuum Concentrate.By chromatography (SiO2, the DCM of 0-20% solution in heptane) and purification residue, obtain title compound (0.801g, 29%).LCMS(ES+)233.0(M+H)+。
Intermediate 136
[2-(1-hydroxyl-1-methyl-ethyl) is phonetic for (1R, 3S)-1-[2-chloro-6-(difluoro-methoxy) phenyl] the fluoro-7-of-6- Pyridine-5-base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
By method C from intermediate 124 (4.61g, 10.30mmol) and 2-[5-(4,4,5,5-tetramethyl-1,3,2-two Oxa-bora Pentamethylene .-2-base) pyrimidine-2-base] propane-2-alcohol (3.00g, 11.330mmol) prepare intermediate 136 (3.6g, 69%).LCMS(ES+)RT 1.91min。505.15/507.15(M+H)+。
Intermediate 137 method I
(1R) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-3,8-two fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles
Intermediate 110 (1.0g, 2.420mmol) is dissolved in DCM (30mL).At 0 DEG C, it is added dropwise over DAST (0.384mL, 2.904mmol, 1.2 equivalent).Reactant mixture is stirred 0.5h at 0 DEG C.Add saturated NaHCO3Solution, and will Mixture DCM (2 × 100mL) extracts, and by dried over sodium sulfate for the organic layer of merging, concentrate in a vacuum, obtain title Compound (0.94g, 83%).LCMS acid (ES+)415.0/417.0(M+H)+。
Intermediate 138 and 139
The bromo-1-of (1R, 3S or R)-7-[2-(difluoro-methoxy) phenyl]-3,8-two fluoro-2,3-dihydro-1H-pyrrolo-[1, 2-a] benzimidazole and the bromo-1-of (1R, 3R or S)-7-[2-(difluoro-methoxy) phenyl]-3,8-two fluoro-2,3-dihydro-1H-pyrrole Cough up also [1,2-a] benzimidazole
By chiral chromatography purification intermediate 137, and at Chiralpak IA (50*266mm* under the conditions of SFC Mm, flow velocity 360mL/min, 25 DEG C, CO2/2-PrOH 80/20, the solution of 66g/L concentration of injection 9mL) upper separate titled Compound.
Collect the enantiomer (RT 6min) of first eluting, and described fraction is evaporated to obtain (enantiomer 1) (intermediate 138).
Collect the enantiomer (RT 12.19min) of the second eluting, and described fraction is evaporated to obtain (enantiomerism Body 2) (intermediate 139).LCMS(ES+)417.19(M+H)+。
Intermediate 140
9-(5-Bromopyrimidine-2-base)-3,7-dioxa-9-azabicyclo [3.3.1] nonane
By 3,7-dioxa-9-azabicyclo [3.3.1] nonane (0.39g, 3.0mmol) and 5-bromo-2-chloropyrimide (0.61g, 3.0mmol) is dissolved in ethanol (5mL).Add triethylamine (0.47mL, 3.3mmol), and reactant mixture is existed 80 DEG C of heating 18h.Reactant mixture is concentrated in a vacuum, is dissolved in EtOAc, and remaining initiation material is leached.Logical Cross chromatography (SiO2, the EtOAc of 0-100% solution in DCM) purification residue, obtain title compound (297mg, 35%).1H NMR(400MHz,CDCl3)δppm 8.33(s,2H),4.48(s,2H),4.11(d,J 11.2Hz,4H),3.93 (d,J 11.8Hz,4H)。LCMS(ES+)286MH+。
Intermediate 141
N-[(4-bromophenyl) (methyl) oxo-λ 6-sulfurous alkyl]-2,2,2-trifluoroacetamide
In room temperature to 1-bromo-4-methanesulfinyl benzene (5g, 22.8mmol), MgO (3.68g, 91.3mmol), four (second Acid group closes (acetato)-κ O) two rhodiums (Rh-Rh) (0.25g, 0.57mmol) and 2,2,2-trifluoroacetamide (5.16g, 45.6mmol) suspension in anhydrous DCM (150mL) adds double (acetoxyl group) (phenyl)-λ～3～-iodine alkane (iodane)(11.03g,34.2mmol).Reactant is stirred at room temperature 18h.Reactant mixture is filtered over celite, and Filter cake DCM (30mL) is washed.Concentrated filtrate in a vacuum, and by column chromatography (SiO2, the EtOAc of 0-100% is in heptan Solution in alkane) purification, obtain the title compound (5.7g, 97%) as light yellow oil.1H NMR(250MHz,CDCl3)δ ppm 7.92-7.75(m,4H),3.45(s,3H)。LCMS(ES+)RT1.27min,330.0/332.0(M+H)+。
Intermediate 142
(4-bromophenyl)-imino-methyl-oxo-λ 6-sulfane
In the intermediate 141 (5.7g, 17.1mmol) solution in MeOH (100mL) add potassium carbonate (11.6g, 83.7mmol).Reactant is stirred at room temperature 2h.Mixture is concentrated in a vacuum, then dilutes with water (50mL).By product Extract with EtOAc (3 × 100mL).The organic fraction of merging is dried (MgSO4) and concentrate in a vacuum, obtain as yellow The title compound (4.00g, 96%) of oil.1H NMR(500MHz,CDCl3)δppm 7.89-7.83(m,2H),7.70-7.65 (m,2H),3.09(s,3H),2.65(s,1H)。LCMS(ES+)RT 0.81min,234.0/236.0(M+H)+。
Intermediate 143
Imino-methyl-oxo-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base) benzene Base]-λ-6-sulfane
By intermediate 142 (4g, 15.4mmol) at anhydrous 1,4-bis-Solution 4,4,4', 4', 5 in alkane (80mL), 5,5', 5'-prestox-2,2'-two-1,3,2-dioxaborolan alkane (4.69g, 18.5mmol) and potassium acetate (4.53g, 46.1mmol) process.Mixture is the most thoroughly deaerated 10 minutes, is subsequently adding that double [3-(diphenylphosphino) ring is amyl- 2,4-diene-1-base] ferrum；Dichloromethane；Palladium chloride (0.63g, 0.77mmol).Reactant is stirred 75min at 80 DEG C.Will Reactant concentrates in a vacuum, is re-dissolved in EtOAc (200mL), and washs with water (100mL).By aqueous phase EtOAc (50mL) heavily extract, and the organic extract saline (100mL) merged is washed, be dried (Na2SO4) and concentrate in a vacuum. Residue is ground together with heptane, obtains the title compound (3.05g, 60%) as brown solid.1H NMR (500MHz,CDCl3)δppm 8.02-7.98(m,4H),3.09(s,3H),1.36(s,12H)。
Intermediate 144
5-bromo-2-methanesulfon yl pyridines
In room temperature by NaIO4(9.56g, 44.69mmol) adds 5-bromo-2-(methyl as the slurry in water (10mL) Sulfanyl) in the pyridine (2.4g, 11.76mmol) agitating solution in acetic acid (40mL).Mixture is stirred at room temperature 2h.Should After time, form colourless precipitate.Being processed by mixture use water (50mL), hereafter precipitate dissolves.By the acidity of aqueous Mixture alkalizes by adding unsaturated carbonate aqueous solutions of potassium, and is extracted by product EtOAc (3 × 50mL).By merge Organic facies 10% sodium thiosulfate solution (50mL) washs, is dried (Na2SO4) and reduce (reduced) in a vacuum, To the crude product (2.52g) as amber glass, it is solidified on standing.By chromatography (SiO2, the EtOAc of 0-100% Solution in heptane) purification, obtain the title compound (2.04g, 79%) as faint yellow oil.δH(500MHz,CDCl3) 8.68(d,J 2.0Hz,1H),8.08(dd,J 8.3,2.2Hz,1H),7.93(d,J 8.3Hz,1H),2.84(s,3H)。
Intermediate 145-147
The similar method of method used and describe, from the intermediate listed or from prepared by the initiation material being obtained commercially State intermediate.
Intermediate 148 and 149
The bromo-1-of (1R, 3R)-7-[2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzo miaow Azoles-3-alcohol and the bromo-1-of (1R, 3S)-7-[2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzo miaow Azoles-3-alcohol
According to the operation described about intermediate 110, use the bromo-2-of 4-fluoro-1-nitro-benzene as examination in the first step Agent, the preparation bromo-1-of (1R)-7-[2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3- Alcohol.
By under the conditions of SFC Lux-Cell-4 (50*291mm*mm, flow velocity 360mL/min, 25 DEG C, CO2/EtOH 75/25, the solution of the 33g/L concentration of injection 9.1mL) the upper bromo-1-of purification (1R)-7-[2-(difluoro-methoxy) phenyl]-2,3- Dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol, separates title compound.
Collect the enantiomer (RT 3min) of first eluting, and described fraction is evaporated to obtain (diastereomer 1) (intermediate 148).
Collect the enantiomer (RT 5min) of the second eluting, and described fraction is evaporated to obtain (diastereomer 1) (intermediate 149).
Intermediate 150
2-[the bromo-1-of (1R, 3R)-7-(2-difluoro-methoxy-phenyl)-2,3-dihydro-1H-benzo [d] pyrrolo-[1,2- A] imidazo-3-yl epoxide]-ethanol
NaH (53mg, 1.33mmol, 60% are in mineral oil) is added intermediate 148 (500mg, 1.27mmol) at DMF (1mL) in the solution in, and reactant mixture is stirred at room temperature 30 minutes.Add 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans (279mg, 1.27mmol), and reactant mixture is stirred 3h, and distribute between EtOAc (4mL) and water (4mL).Separate each Phase, and organic phase washed with water (3 × 2mL) is washed.By organic facies through Na2SO4It is dried and concentrates in a vacuum.Residue is dissolved In MeCN (50mL), add 2N HCl (10mL), and mixture is stirred at room temperature 45 minutes.Evaporation, lyophilization and logical Cross preparation HPLC chromatography (Prep-C18 silica gel, MeCN/ water: the gradient from 30/70 to 70/30) purification, obtain titled Compound (420mg, 75.6%)；LCMS(ES+)RT 1.71min,438.99(M+H)+。
Intermediate 151
3-[the bromo-1-of (1R, 3R)-7-(2-difluoro-methoxy-phenyl)-2,3-dihydro-1H-benzo [d] pyrrolo-[1,2- A] imidazo-3-yl epoxide]-propane-1-alcohol
By the similar approach described about the synthesis of intermediate 150, from intermediate 148 (600mg, 1.52mmol) and 2- (3-bromine propoxyl group) tetrahydrochysene-2-H-pyrans (339mg, 1.52mmol) prepares title compound (420mg, 61%).LCMS(ES+) RT 1.73min,453.02(M+H)+。
Intermediate 152
2-[[the bromo-1-of (1R, 3R)-7-[5-chloro-2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole-3-base] epoxide] ethanol
As described in the synthesis about intermediate 150, prepare title compound from intermediate 161 (350mg, 0.81mmol) (300mg, 77.7%).LCMS(ES+)RT 1.77min,473.04(M+H)+。
Intermediate 153
1-{2-[the bromo-1-of (1R, 3R)-7-(2-difluoro-methoxy-phenyl)-2,3-dihydro-1H-benzo [d] pyrrolo-[1, 2-a] imidazo-3-yl epoxide]-ethyl }-pyrrolidin-2-one
0 DEG C add in the intermediate 148 (300mg, 0.76mmol) solution in DMF (2mL) NaH (32mg, 0.80mmol；60% in mineral oil).Mixture is stirred 30 minutes at 0 DEG C.Add 1-(2-bromomethyl) pyrrolidin-2-one (153mg, 0.76mmol), and stir the mixture for other 30 minutes.NaH (32mg, 0.80mmol is added at 0 DEG C；60% in ore deposit In thing oil).Mixture 0 DEG C of stirring 30 minutes and is added 1-(2-bromomethyl) pyrrolidin-2-one (153mg, 0.76mmol), And mixture is stirred for 30 minutes.This operation is repeated 5 times.By reactant mixture between EtOAc (4mL) and water (4mL) Distribution, separates each phase, and is washed by organic phase washed with water (3 × 2mL).By organic facies through Na2SO4It is dried and concentrates in a vacuum.Logical Cross column chromatography (SiO2, the MeOH of 5% solution in DCM) and purification residue, obtain desired product (100mg, 26%). LCMS(ES+)RT 0.816min,506.05(M+H)+。
Intermediate 154
N-[[5-chloro-2-(difluoro-methoxy) phenyl] methylene]-2-methyl-propan-2-sulfenamide
The method described according to the preparation about intermediate 116, from 5-chloro-2-difluoro-methoxy-benzaldehyde and (S)- (-)-t-butyl sulfonamide prepares title compound.
Intermediate 155
(3R)-3-[[(S)-terf-butylsulfinyl] amino]-3-[5-chloro-2-(difluoro-methoxy) phenyl] ethyl propionate
The method described according to the preparation about intermediate 117, prepares title compound from intermediate 154.
Intermediate 156
(3R)-3-amino-3-[5-chloro-2-(difluoro-methoxy) phenyl] propionate hydrochloride
The method described according to the preparation about intermediate 118, prepares title compound from intermediate 155.
Intermediate 157
(R)-ethyl-3-((5-bromo-2-nitrobenzophenone) amino)-3-(5-chloro-2-(difluoro-methoxy) phenyl) propionic ester
The method described according to the preparation about intermediate 119, from the bromo-2-of intermediate 156 and 4-fluoro-1-nitro-benzene system Standby title compound.
Intermediate 158
(3R)-3-(5-bromo-2-nitro-anilino)-3-[5-chloro-2-(difluoro-methoxy) phenyl] propionic aldehyde
It is added dropwise in the intermediate 157 (10g, 20.3mmol) solution in anhydrous THF (50mL) at-78 DEG C DIBAL-H (40.5mmol, the 1M solution in toluene), and by mixture-78 DEG C of stirrings.After-78 DEG C of 3h, add another Outer DIBAL-H (40.5mmol, the 1M solution in toluene).After stirring other 1h at-78 DEG C, by reactant mixture chlorine Change aqueous ammonium quencher and warm to room temperature.After diluting further with aqueous ammonium chloride solution, add DCM.NaCl is added water After in mutually, organic facies is separated, with NaCl solution washing with through Na2SO4It is dried and concentrates in a vacuum, obtaining title product (it quantitatively), is used for next step by 9.99g without further purification.
Intermediate 159
(4R)-4-((5-bromo-2-nitrobenzophenone) amino)-4-(5-chloro-2-(difluoro-methoxy) phenyl)-2-((trimethyl Silicyl) epoxide) butyronitrile
ZnI is added in the intermediate 158 (9.99g, 22.22mmol) solution in DCM (50mL)2(723mg, 2.22mmol), TEA (0.313mL, 2.22mmol) and TMSCN (6.08ml, 44.44mmol).Reactant mixture is stirred in room temperature Mixing 1h, organic facies is also separated by dilute with water.By organic layer with NaCl solution washing with through Na2SO4It is dried and the denseest Contracting, obtains title product (11g, 90%).
Intermediate 160
(R) the bromo-1-of-7-(5-chloro-2-difluoro-methoxy-phenyl)-2,3-dihydro-1H-benzo [d] pyrrolo-[1,2-a] Imidazoles-3-alcohol
In the intermediate 159 (11g, 20.04mmol) solution in EtOH (80ml), add SnCl2(19.39g, 100.21mmol), and by reactant mixture 3h is heated at 80 DEG C.By reactant mixture use water (80mL) quencher, and use 2M KOH alkalizes to pH 8.Mixture EtOAc is diluted.After filtration, organic facies is separated, wash by NaCl solution, warp Na2SO4It is dried and concentrates in a vacuum.By chromatography (SiO2, the EtOAc of 30% solution in heptane) and purification residue, Obtain title compound (4.5g, through 3 step 52% yields).
Intermediate 161 and 162
The bromo-1-of (1R, 3R)-7-[5-chloro-2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles-3-alcohol and the bromo-1-of (1R, 3S)-7-[5-chloro-2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole-3-alcohol
By chiral chromatography (Chiralpak AD, 400 × 100mm, 20 μM, heptane/ethanol=3/1, flow velocity= 300ml/min) separation of intermediates 160.First the diastereomer 1 (9min) of eluting: intermediate 161 (1.75g, 20%). LCMS(ES+)RT 1.75min,429(M+H)+。
The diastereomer (16.3min) of the second eluting: intermediate 162, (1.98g, 23%).LCMS(ES+)RT 1.74min,428.96(M+H)+。
Intermediate 163
(1R, 5S)-3-[5-[(1R, 3R)-1-[2-(difluoro-methoxy) phenyl]-6-fluoro-3-hydroxyl-2,3-dihydro-1H- Pyrrolo-[1,2-a] benzimidazole-7-base] pyrimidine-2-base]-3-azabicyclo [3.2.1] octane-8-methyl formate
By method C, prepare mark from embodiment 160 (500mg, 1.21mmol) and intermediate 40 (493mg, 1.69mmol) Topic compound (501mg, 71%).LCMS(ES+)RT 1.49min,580.0(M+H)+
Intermediate 164
The bromo-1-of (1R, 3R or S)-7-[2-(difluoro-methoxy) phenyl]-8-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] Benzimidazole-3-alcohol
Intermediate 107 (40.5g, 1.0 equivalents) and iron powder (3 equivalent) are dissolved in AcOH (70mL), and reaction is mixed Compound stirs 1h at 100 DEG C.In room temperature, add water, mixture DCM is extracted, the saturated NaHCO of organic facies that will merge3 Solution washing, is dried (MgSO4), and concentrate in a vacuum.Use SFC condition Lux-Cell-4 (50*261mm*mm, Flow velocity 360mL/min, 25 DEG C, CO2+ 20%MeOH, the solution of 30g/L concentration of injection 3.66mL) on pass through chiral chromatography Purification residue.Collect the diastereomer (RT 5.15min) of first eluting, and described fraction is evaporated to obtain title Compound 1R, 3R or S diastereomer (550mg, 64.4%).
Intermediate 165 method K
4-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-8-[2-(1-hydroxyl-1-methyl-ethyl) pyrimidine-5-base]-3,4- Dihydro-1H-pyrazine also [1,2-a] benzimidazolyl-2 radicals-t-butyl formate
In microwave container (20ml), embodiment 12 (300mg, 586 μm ol) is dissolved in Isosorbide-5-Nitrae-twoIn alkane (8mL) And by solution purification for argon.It is subsequently adding sodium carbonate (124mg, 1.17mmol), 2-(5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan alkane-2-base) pyrimidine-2-base) propane-2-alcohol (186mg, 703 μm ol) and water (2mL).By this mixture Again by purification for argon, it is subsequently adding three (dibenzalacetone) two palladium (0) complex (54mg, 59 μm ol) and tri-tert four Borofluoride (5mg, 18 μm ol).100 DEG C of heating 15 minutes and after being cooled to room temperature in microwave oven, add saline and EtOAc, and after phase separation, aqueous phase EtOAc is extracted 2 times.The organic phases washed with brine that will merge, does through sodium sulfate Dry, filter and concentrate in a vacuum.By preparation HPLC (M2d) purification residue, obtain title compound (211mg, 63%).LCMS[M 1b](ES+)RT 1.82min,570.3(M+H)+。
Embodiment 1
The bromo-1-of 7-(2,5-3,5-dimethylphenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method B, from the intermediate 4 (0.09g, 0.23mmol) solution in AcOH (1mL) and iron powder (0.06g, 1.15mmol) prepare title compound (0.09g, 38%).1H NMR(400MHz,CDCl3)δ7.63(m,1H),7.35(dd,J 8.5,1.5Hz,1H),7.17(m,1H),7.04(m,2H),6.48(m,1H),5.65(m,1H),3.21(m,3H),2.53(m, 1H),2.39(m,3H),2.22(m,3H)。LCMS(ES+)RT 1.65min,341.0/343.0(M+H)+。
Embodiment 2 (method C)
1-(2,5-3,5-dimethylphenyl)-7-(6-methoxyl group-3-pyridine radicals)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles
To embodiment 1 (0.08g, 0.23mmol) and 6-methoxypyridine 3-ylboronic acid (0.04g, 0.26mmol) at 1,4- TwoSolution in alkane/water (6mL, 10:1) adds K2CO3(0.10g,0.70mmol).Reactant mixture is deaerated 10 points Clock, is subsequently adding Pd (PPh3)4(0.003g,0.01mmol).Reactant mixture is heated 20h at 100 DEG C.By reactant mixture Dilute with EtOAc (10mL), wash with water (10mL), saline (10mL), and organic layer is separated, is dried (Na2SO4) and very Aerial concentration.By preparation HPLC purification residue, obtain title compound (0.01g, 15%).1H NMR(400MHz, CDCl3)δ8.26(d,J 2.3Hz,1H),7.84(m,1H),7.70(m,1H),7.43(dd,J 8.4,1.5Hz,1H),7.17 (m,1H),7.06(m,1H),6.99(s,1H),6.80(m,1H),6.61(m,1H),5.72(m,1H),3.97(m,3H),3.26 (m,3H),2.55(m,1H),2.43(m,3H),2.18(s,3H)。LCMS(ES+)RT 1.62min,370.0(M+H)+。
Embodiment 3-13
Following embodiment is prepared from the precursor specified by method B.
Embodiment 14-102
Use suitable borate or boric acid, using method C from the precursor specified (from that be obtained commercially or as in the middle of above Preparation described in body) prepare following embodiment.
Embodiment 103 (method D)
5-[1-(2-aminomethyl phenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-7-base] pyridine-2 (1H)- Ketone
HBr aqueous solution (2mL) is added in the embodiment 18 (0.10g, 0.28mmol) solution in EtOH (2mL).Will Reactant heats 18h at 95 DEG C.Reactant mixture is concentrated in a vacuum, and residue EtOAc (10mL) is diluted, with full And NaHCO3Organic layer is also separated, is dried (Na by the washing of aqueous solution (10mL), water (10mL), saline (10mL)2SO4) and very Aerial concentration.By preparative TLC purification residue, obtain title compound (0.06g, 62%).1H NMR(400MHz, CDCl3)δ12.85(s,1H),7.77(d,J 8.4Hz,1H),7.73-7.63(m,1H),7.44(d,J 2.7Hz,1H), 7.32-7.01(m,4H),6.85(d,J 1.8Hz,1H),6.63(dd,J 16.2,8.6Hz,2H),5.70(dd,J 7.5, 4.9Hz,1H),3.29-3.03(m,3H),2.61-2.36(m,4H)。LCMS(ES+)RT 1.35min,342.1(M+H)+。
Embodiment 104
5-(1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-7-base) pyridine-2 (1H)-one
By method D, from embodiment 20 (0.10g, 0.02mmol) and HBr aqueous solution prepare title compound (0.07g, 71%).1H NMR(400MHz,DMSO-d6)δ7.75(d,J 8.4Hz,1H),7.64(dd,J 9.5,2.6Hz,1H),7.51- 7.28(m,4H),7.33-7.06(m,3H),6.82(d,J 1.8Hz,1H),6.61(d,J 9.4Hz,1H),5.48(t,J 6.7Hz,1H),3.30-3.06(m,3H),2.70-2.51(m,1H)。LCMS(ES+)RT 1.21min,328.1(M+H)+。
Embodiment 105
Enantiomer 1:(1S or R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)- 2,3-dihydro-1H-imidazo [1,2-a] benzimidazole
By under the conditions of SFC Chiralpak IA (50*266mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%MeOH, the solution of the 8g/L concentration of injection 5mL) upper chirally purified, separate title compound from embodiment 22.First eluting Enantiomer (6.88min).
Embodiment 106
Enantiomer 2:(1R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)- 2,3-dihydro-1H-imidazo [1,2-a] benzimidazole
By under the conditions of SFC Chiralpak IA (50*266mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%MeOH, the solution of the 8g/L concentration of injection 5mL) upper chirally purified, separate title compound from embodiment 22.Second eluting Enantiomer (9.06min).
Embodiment 107
Enantiomer 1:(1S or R)-1-[2-(difluoro-methoxy) phenyl]-7-(4-methylsulfonyl phenyl)-2,3- Dihydro-1H-imidazo [1,2-a] benzimidazole
By under the conditions of LC Lux-Cell-2 (76*370mm*mm, flow velocity 200mL/min, 30 DEG C, EtOH 100%, the solution of the 1.8g/L concentration of injection 10mL) upper chirally purified, prepare title compound from embodiment 23, obtain title Compound (9mg, 50%, the first enantiomer of eluting, RT 15min) and the enantiomer (RT of the second eluting 24min)。LCMS(ES+)RT3.4min,456.3(M+H)+。
Embodiment 108 (method F)
Enantiomer 2:(1R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(6-piperazine-1-base-3-pyridine Base)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
Embodiment 24 (1.0g, 1.73mmol, 1 equivalent) is dissolved in 1,4-bis-In alkane (25mL/mmol), and add The HCl/1,4-bis-of 4MAlkane (0.436mL, 1 equivalent), is subsequently added water (2mL).Mixture is stirred at room temperature 4h, will be anti- Answer thing to concentrate in a vacuum, and residue is dissolved in DCM (100mL) and water (50mL).Organic layer is abandoned, and by water-soluble Liquid layer Na2CO3Alkalization, and extract with DCM (2 × 100mL).Organic layer is separated, is dried (MgSO4) and concentrate in a vacuum, Obtain the title compound (650mg, 79%) as foam.1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.64(dt,J 8.8Hz,J 2.1Hz,1H),7.49(d,J 11.2Hz,1H),7.35(td,J 7.7Hz,J 1.2Hz,1H),7.21(d,J 8.1Hz,1H),7.13(t,J 7.3Hz,1H),6.84(d,J 7.6Hz,1H),6.80(d,J 6.7Hz,1H),6.66(d,J 8.8Hz,1H),6.61(t,J 73.2Hz,1H),5.84(dd,J 7.5Hz,J 4.8Hz,1H),3.54(m,4H),3.19(m, 3H),3.00(m,4H),2.55(m,1H)。LCMS(ES+)RT2.99min,480(M+H)+。
Embodiment 109
Enantiomer 2:5-[(1R or S)-1-[2-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo- [1,2-a] benzimidazole-7-base]-1H-pyridin-2-ones
By method D, prepare title compound from embodiment 25 (26mg, 0.064mmol, 1.0 equivalent), obtain as nothing The title compound (17mg, 65%) of color vitreous solid.1H NMR(400MHz,CDCl3)δ7.61(d,J 9.4Hz,1H), 7.49(d,J 11.3Hz,1H),7.45(d,J 1.6Hz,1H),7.37(t,J 7.4Hz,1H),7.24(t,J 8.6Hz,1H), 7.14(t,J 7.6Hz,1H),6.78(d,J 7.7Hz,1H),6.75(d,J 6.8Hz,1H),6.65(t,J 73.4Hz,1H), 6.60(d,J 9.4Hz,1H),5.84(m,1H),3.21(m,3H),2.56(m,1H).LCMS (condition #AC, ES+)RT 3.13min,412.3(M+H)+, 96.3% purity.LCMS(ES+)RT 3.71min,412.1(M+H)+。
Embodiment 110
Enantiomer 2:1-[4-[5-[(1R or S)-1-[2-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H- Pyrrolo-[1,2-a] benzimidazole-7-base]-2-pyridine radicals] piperazine-1-base] ethyl ketone
To embodiment 108 (0.03g, 0.067mmol) and PS-DIPEA (N ° of 800280,3.53mmol/g of Argonaut, 0.035g, 0.125mmol) solution in DCM (5mL/g) adds chloroacetic chloride (5.4mg, 0.068mmol, 1.1 equivalent) exist Solution in DCM (0.1mL).Reactant is stirred at room temperature 2h, reactant mixture is leached and concentrated filtrate in a vacuum.Logical Cross column chromatography (SiO2, the ammonia of 0-3% solution/DCM in methanol) purification residue, obtain title compound (12mg, 36%).1H NMR(400MHz,CDCl3)δ8.21(s,1H),7.66(m,1H),7.50(d,J11.2Hz,1H),7.35(m, 1H),7.21(d,J 8.0Hz,1H),7.13(t,J 7.5Hz,1H),6.64(m,4H),5.85(m,1H),3.74(m,2H), 3.65(m,2H),3.58(m,2H),3.53(m,2H),3.20(m,3H),2.55(m,1H),2.15(s,3H)。LCMS(ES+)RT 3.4min,522.2(M+H)+。
Embodiment 111
Enantiomer 2:(1R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-[6-(4-methyl piperazine-1- Base)-3-pyridine radicals]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By embodiment 108 (0.03g, 0.067mmol) and formaldehyde (33 μ L, 0.43mmol, 7 equivalent) at MeOH (5mL/g) In solution stirring 4h.Add MP-CNBH3(Biotage, ref 800406, loads 2.49mmol/g, 70.5mg, 0.173mmol, 2.7 equivalents).Reactant is stirred at room temperature 20h.Add formaldehyde (0.1mL, 1.23mmol, 18 equivalent), subsequently Add NaBH3CN (10mg, 1.6mmol, 23 equivalent).Reactant is heated 2h at 60 DEG C.Mixture is leached and in a vacuum Concentrated filtrate.By column chromatography (SiO2, the ammonia of 0-5% solution/DCM in methanol) and purification residue, obtain titled Compound (20mg, 78%).1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.63(dt,J 8.7,2.0Hz,1H),7.48 (d,J 11.2Hz,1H),7.34(m,1H),7.21(d,J 8.2Hz,1H),7.12(t,J 7.6Hz,1H),6.64(m,4H), 5.84(m,1H),3.59(m,4H),3.19(m,3H),2.55(m,5H),2.35(s,3H)。LCMS(ES+)RT2.9min, 494.3(M+H)+。
Embodiment 112
Enantiomer 2:(1R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-[6-(4-methyl sulphonyl piperazine Piperazine-1-base)-3-pyridine radicals]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
To embodiment 108 (0.03g, 0.067mmol) and PS-DIEA (Argonaut Technologies, N ° 800280, Load 3.53mmol/g, 70mg, 0.250mmol, 4 equivalent) solution in DCM (5mL/g) adds mesyl chloride (16.2mg, 0.125mmol, 2.2 equivalent) solution in DCM (0.1mL).Reactant is stirred at room temperature 2h.By reactant Leach and concentrated filtrate in a vacuum.By column chromatography (SiO2, the ammonia of 0-5% solution/DCM in methanol) and purification remnants Thing, obtains title compound (20mg, 57%).1H NMR(400MHz,CDCl3)δ8.21(d,J 0.5Hz,1H),7.67(d,J 9.1Hz,1H),7.49(m,1H),7.35(m,1H),7.22(d,J 8.3Hz,1H),7.13(t,J 7.4Hz,1H),6.66(m, 4H),5.90(m,1H),3.70(m,4H),3.26(m,7H),2.80(s,3H),2.55(m,1H)。LCMS(ES+)RT 3.8min,558.3(M+H)+。
Embodiment 113
Enantiomer 1:(1R or S)-7-[6-(chloromethyl)-3-pyridine radicals]-1-phenyl-2,3-dihydro-1H-pyrrolo- [1,2-a] benzimidazole
0 DEG C to embodiment 33 (20mg, 0.059mmol) at CHCl3(0.2mL) solution in adds SOCl2 (0.021mL, 35mg, 0.29mmol, 5.0 equivalent).Then mixture is heated 3h at 60 DEG C.Add saturated NaHCO3Water-soluble Liquid, extracts mixture DCM, is dried (MgSO4) and concentrate in a vacuum, obtain title compound (12mg), by its without Be further purified for next step.LCMS(ES+)RT 4.58min,360.2/362.1(M+H)+。
Embodiment 114
Enantiomer 1:(1R or S)-7-[6-(sulfonyloxy methyl ylmethyl)-3-pyridine radicals]-1-phenyl-2,3-dihydro- 1H-pyrrolo-[1,2-a] benzimidazole
By embodiment 113 (22mg, 0.06mmol, 1.0 equivalent), methane sulfinic acid sodium (26mg, 0.25mmol, 4 equivalent), NaI (1mg, 0.07mmol, 0.1 equivalent) in EtOH (0.75mL) at microwave radiation under (300 watts) 100 DEG C heat 15min. By reactant mixture dilute with water, and extract with DCM.Organic substance is dried (Na2SO4) and concentrate in a vacuum.Pass through column chromatography Method (SiO2, the ammonia of 2-5% solution/DCM in methanol) and purification residue, obtain the title compound as white solid (14mg, 56%).1H NMR(400MHz,CDCl3)δ8.67(d,J 1.9Hz,1H),7.82(d,J 8.3Hz,1H),7.80 (dd,J 7.9Hz,J 1.9Hz,1H),7.48(d,J 8.0Hz,1H),7.35-7.44(m,4H),7.21(d,J 2.0Hz, 1H),7.19(t,J 1.4Hz,1H),6.98(s,1H),5.51(t,J 6.4Hz,1H),4.42(s,2H),3.29(ddd,J 14.3Hz,J 8.1Hz,1H),3.12-3.24(m,2H),2.92(s,3H),2.63(m,1H)。LCMS(ES+)RT 3.7min, 404.3(M+H)+。
Embodiment 115
(1R or S, 3R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(6-methyl sulphonyl-3-pyridine radicals)- 2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
Solution A is prepared with the embodiment 32 (1.07mg, 0.00226mmol, 1 equivalent) solution in 400 μ L MeCN, and Dilute with 1.6mL water to reach 0.5mg/mL.From D-Glucose 6-disodium hydrogen phosphate salt hydrate (2.113g, 100mM), B-nicotinoyl Amine adenine-dinucleotide phosphate ester (533.5mg, 10mM) and 700 μ L MgCl2.6H2O (1M) is at 69mL phosphate buffer Solution in (100mM, pH=7.4) prepares solution B.In teat glass, by 5.5mL phosphate buffer, 1mL mice microgranule Body (the Male CD1 consolidated material of the 1042 of 20mg/mL, M1000), 1mL solution A, 2.5mL solution B, 12 μ L G6Ps Dehydrogenase at 37 DEG C swelling lower incubation 30 minutes.By add MeCN (5mL) stop incubation, and by test tube 3000rpm from The heart 15 minutes.By preparative 2D LCMS from supernatant purification title compound, obtain the title compound as white solid (116 μ g, 20%).1H NMR(400MHz,DMSO-d6)δ.8.81(s,1H),8.19(d,J 8.3Hz,1H),8.09(d,J 8.1Hz,1H),7.72(d,J 11.7Hz,1H),7.40(d,J 7.3Hz,1H),7.36(t,J 74.0Hz,1H),7.30(d,J 7.9Hz,1H),7.19(m,2H),6.96(d,J 7.6Hz,1H),6.21(bs,1H),5.87(dd,J 7.9Hz,J 4.8Hz, 1H),5.27(m,1H),3.49(dt,J 13.6Hz,J 7.8Hz,1H),3.30(s,3H),2.30(dt,J1 13.3Hz,J2 4.3Hz,1H)。LCMS(ES+)RT 3.83min,490.2(M+H)+。
Embodiment 116
[the bromo-1-of 7-[2-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole- 3-yl] acetas
Intermediate 99 (37g, 85.8mmol) is dissolved in acetic anhydride (160mL).Add ZnCl2(11.7g, 85.8mmol, 1.0 equivalents), and mixture is stirred at room temperature 2min, then heat 45min at 90 DEG C.Mixture is cooled to 0 DEG C, it is subsequently adding water (200mL) and EtOAc (200mL).After adding 50mL water, by mixture decant lentamente.By water Solution layer EtOAc (50mL 2 ×) extracts.The organic layer NaOH aqueous solution (1N, 2 × 100mL) merged is washed, then Wash with saline, be then dried (MgSO4), concentrate in a vacuum, obtain the black oil (52g) as residue, passed through Column chromatography (SiO2, the ammonia of 0-1% solution/DCM in methanol) and purification.The fraction containing expectation compound merged is led to Cross column chromatography (SiO2, 0-35%EtOAc/ heptane) purification, obtain title compound (8.3g, 21%, as 4 kinds of isomers Mixture).LCMS(ES+)RT 4.9min,455.1/457.1.1(M+H)+。
Embodiment 117
1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)-2,3-dihydro-1H-pyrrolo- [1,2-a] benzimidazole-3-alcohol
By embodiment 34 (900mg, 1.70mmol) and K2CO3(355mg, 2.5mmol, 1.5 equivalent) pours MeOH into (3.4mL) in, and mixture is stirred at room temperature 2h, reactant mixture is concentrated in a vacuum.Add water (2mL) and EtOAc (10mL).Extract by mixture decant and by aqueous layer EtOAc.The organic layer of merging is dried (MgSO4), in a vacuum Concentrating, obtain the title compound (886mg, 89%) as water white oil, it is further purified for next step without any. LCMS(ES+)RT 3.9min,489.2(M+H)+。
Embodiment 118,119,120 and 121
(1R or S, 3R or S) (diastereomer 1)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methyl sulphur Aminosulfonylphenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol, (1R or S, 3S or R) (diastereomer 2)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] Benzimidazole-3-alcohol, (1R or S, 3S or R) (diastereomer 3)-1-[2-(difluoro-methoxy) phenyl]-6-fluoro-7-(4- Methylsulfonyl phenyl)-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol and (1S or R, 3S or R) (diastereomeric Isomer 4)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)-2,3-dihydro-1H-pyrrolo- [1,2-a] benzimidazole-3-alcohol
By under the conditions of LC Lux-Cell-4 (76*265mm*mm, flow velocity 200mL/min, 30 DEG C, EtOH/ heptane 1/1, the solution of the 1.8g/L concentration of injection 83mL) upper purification embodiment 117, separate title compound.
Collect the enantiomer (RT 12.89min) of first eluting, and (diastereomeric is different to obtain by the evaporation of described fraction Structure body 1) (1R or S, 3R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)-2,3-two Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol (115mg, 14%, embodiment 118).1H NMRδ:7.97(d,J 8.4Hz,2H),7.67(m,3H),7.40(m,1H),7.31(m,1H),7.19(m,1H),7.07(d,J 6.9Hz,1H),6.99 (d,J 7.7Hz,1H),6.14(d,J 4.8Hz,1H),5.87(dd,J 8.0Hz,J 4.8Hz,1H),5.27(m,1H),3.49 (m,1H),3.24(s,3H),2.30(dt,J 13.5Hz,J 4.4Hz,1H)。LCMS(ES+)RT 3.9min,489.2(M+H)+。
Collect the enantiomer (RT 14.95min) of the second eluting, and (diastereomeric is different to obtain by the evaporation of described fraction Structure body 2) (1R or S, 3S or R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)-2,3-two Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol (110mg, 13%, embodiment 119).LCMS(ES+)RT 3.9min, 489.2(M+H)+。
Collect the enantiomer (RT 21.61min) of the 3rd eluting, and (diastereomeric is different to obtain by the evaporation of described fraction Structure body 3) (1S or R, 3S or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)-2,3-two Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol (135mg, 16%, embodiment 120).LCMS(ES+)RT 3.9min, 489.2(M+H)+。
Collect the enantiomer (RT 29.56min) of the 4th eluting, and (diastereomeric is different to obtain by the evaporation of described fraction Structure body 4) (1S or R, 3R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-(4-methylsulfonyl phenyl)-2,3-two Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol (135mg, 16%, embodiment 121).LCMS(ES+)RT 3.9min, 489.2(M+H)+。
Embodiment 122
Enantiomer 1:(1R or S) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-1,3-thiazoline also [3,4-a] Benzimidazole
According to the method described about intermediate 48 and 49, start to prepare title compound from intermediate 46 (5g), obtain Title compound (1.9g, 43%).1H NMR(400MHz,CDCl3)δ7.49(d,1H,J 8.6Hz),7.28(m,2H),7.13 (d,J 8.1Hz,1H),7.06(t,J 7.5Hz,1H),6.91(s,1H),6.85(d,J 7.5Hz,1H),6.53(m,2H), 4.37(m,1H),4.20(m,1H)。LCMS(ES+)RT 4.8min,397.0/399.0(M+H)+。
Embodiment 123
Enantiomer 2:(1S or R) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-1,3-thiazoline also [3,4-a] Benzimidazole
According to the method described about intermediate 48 and 49, start to prepare title compound from intermediate 47 (5g), obtain Title compound (1.7g, 38%).1H NMR(400MHz,CDCl3)δ7.58(d,J 8.6Hz,1H),7.36(m,2H),7.22 (d,J 8.1Hz,1H),7.15(t,J 7.6Hz,1H),7.00(d,J 1.4Hz,1H),6.93(d,J 7.6Hz,1H),6.62 (m,2H),4.45(m,1H),4.29(m,1H)。LCMS(ES+)RT 4.8min,397(M+H)+。
Embodiment 124
Enantiomer 2:(1R or S)-1-[2-(difluoro-methoxy) phenyl]-7-(6-piperazine-1-base-3-pyridine radicals)- 2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By method F, prepare title compound from embodiment 35 (0.3g, 36.2mmol 1 equivalent) and TFA (2mL) (0.085g, 34%).1H NMR(400MHz,CDCl3)δ8.31(d,J 2.2Hz,1H),7.76(m,1H),7.63(m,1H), 7.35(m,2H),7.22(d,J 7.9Hz,1H),7.12(t,J 7.7Hz,1H),6.98(m,1H),6.86(m,1H),6.63 (m,2H),5.86(m,1H),3.51(m,4H),3.20(m,3H),3.00(m,4H),2.55(m,1H)。LCMS(ES+)RT 2.7min,462(M+H)+。
Embodiment 125
Enantiomer 1:(1R or S) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-3H-[1,3] thiazole also [3,4-a] Benzimidazole 2-oxide
Embodiment 122 (1.0g, 1.0 equivalents) is dissolved in AcOH (10mL).(0.56mL, 2.2 work as to add hydrogen peroxide Amount, 30-37% solution in water), and mixture is stirred at room temperature 18h.Reactant mixture is concentrated in a vacuum, and will Mixture DCM (10mL) dilutes, and washes with water, is dried (MgSO4) and concentrate in a vacuum.By column chromatography (SiO2,0- The ammonia of 2% solution/DCM in methanol) purification residue, obtain the title compound (6mg, 0.6%) as beige solid 。1H NMR(400MHz,CDCl3)δ7.70(m,1H),7.55(m,1H),7.44(m,1H),7.33(m,1H),7.10(m,1H), 6.88(m,1H),6.82(m,1H),6.55(m,1H),4.70(m,1H),4.11(m,1H),4.10(m,1H)。LCMS(ES+)RT 5.85min,413.0/415.0(M+H)+。
Embodiment 126
Enantiomer 2:(1S or R) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-3H-[1,3] thiazole also [3,4-a] Benzimidazole 2-oxide
According to the operation described about embodiment 125, prepare title compound from embodiment 123 (1.50g, 1.0 equivalents). Obtain the title compound (21mg, 1.4%) as brown oil.1H NMR(400MHz,CDCl3)δ.70(m,1H),7.55(m, 1H),7.44(m,1H),7.33(m,1H),7.10(m,1H),6.88(m,1H),6.82(m,1H),6.55(m,1H),4.70(m, 1H),4.11(m,1H),4.10(m,1H)。LCMS(ES+)RT 5.85min,413.0/415.0(M+H)+。
Embodiment 127
7-bromo-1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-base) acetas
Title compound is prepared from intermediate 100 (different as 2 kinds of diastereomeric according to the method described about embodiment 116 The mixture of structure body).LCMS(ES+) RT 4.82 and 4.77min, 371.1/373.1 (M+H)+(ratio: 49/51).
Embodiment 128
7-bromo-1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
Title compound is prepared from embodiment 127 (different as 2 kinds of diastereomeric according to the method described about embodiment 117 The mixture of structure body).LCMS(ES+) RT 4.06 and 4.12min, 329.1/331.1 (M+H)+(ratio 27/72).
Embodiment 129
7-bromo-1-phenyl-1,2-dihydro-3H-pyrrolo-[1,2-a] benzimidazole-3-ketone
By embodiment 128 (1.85g, 5.62mmol) at CHCl3(25mL) solution in have manganese dioxide (10 equivalents, 1h is heated at 60 DEG C in the presence of 56.2mmol).Reactant mixture is cooled down, and filters on bed of diatomaceous earth, and by solid DCM (3 × 50mL), then with MeCN (2 × 25mL) wash.Filtrate is concentrated in a vacuum, obtains brown oil (1.44g).Pass through post Chromatography (SiO2, 25-100%DCM/ hexane class) and purification residue, obtain title compound (390mg, 21%).1H NMR (400MHz,DMSO-d6)δ7.87(d,J 8.8Hz,1H),7.50(dd,J 8.8Hz,J 1.8Hz,1H),7.41(m,5H), 7.26(d,J 1.5Hz,1H),6.02(dd,J 7.3Hz,J 3.6Hz,1H),3.84(dd,J 18.9Hz,J 7.4Hz,1H), 3.19(dd,J 18.9Hz,J 3.6Hz,1H)。LCMS(ES+)RT 4.62min,327.1/329.1(M+H)+。
Embodiment 130
(3Z)-7-bromo-N-hydroxyl-1-phenyl-1,2-dihydro-3H-pyrrolo-[1,2-a] benzimidazole-3-imines
Oxammonium hydrochloride. (0.198g, 2.85mmol) is added embodiment 129 (600mg, 1.84mmol) at EtOH (25mL) With in the solution in pyridine (2mL).The suspension obtained is heated 1h at 65 DEG C.Then mixture is cooled to room temperature and adds EtOAc (200mL), and by mixture use water (3 × 30mL), then with saline (2 × 50mL) washing, it is dried (Na2SO4) and Vacuum concentrates.By residue and Et2The solution of O/EtOAc (15:5) grinds together, and is filtered by solid and do in a vacuum Dry, obtain pale powder (220mg, 35%).1H NMR(400MHz,DMSO-d6)δ7.67(d,J 8.7Hz,1H),7.39 (m,6H),7.24(m,3H),7.16(d,J 1.4Hz,1H),5.86(dd,J 8.3Hz,J 3.5Hz,1H),3.96(dd,J 18.5Hz,J 8.4Hz,1H),3.16(dd,J 18.6Hz,J 3.6Hz,1H)。LCMS(ES+)RT 4.45min,342.0/ 344.0(M+H)+。
Embodiment 131
Enantiomer 1:(1R or S)-1-phenyl-7-[6-(piperazine-1-base) pyridin-3-yl]-2,3-dihydro-1H-pyrrole Cough up also [1,2-a] benzimidazole
By method F, prepare mark from (1:1) mixture (2mL) of embodiment 42 (250mg, 1.0 equivalents) and DCM-TFA Topic compound (157mg, 39.7%).LCMS(ES+)RT 2.5min,396(M+H)+。
Embodiment 132 and 133
Enantiomer 1:(4S or R) the bromo-4-of-7-[2-(difluoro-methoxy) phenyl]-8-fluoro-3,4-dihydro-1H-[1, 4] Piperazine also [4,3-a] benzimidazole；Enantiomer 2:(4R or S) the bromo-4-of-7-[2-(difluoro-methoxy) phenyl]-8- Fluoro-3,4-dihydro-1H-[1,4] Piperazine also [4,3-a] benzimidazole
By under the conditions of SFC Chiralpak AD (50*216mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%MeOH reaches 2.1min, then 40%MeOH for 3.3min, the solution of the 15g/L concentration of injection 16mL) upper chiral separation Embodiment 10, separates title compound.Collect the enantiomer (RT 2.1min) of first eluting, and described fraction is evaporated To obtain (enantiomer 1) (4S or R) bromo-4-of-7-[2-(difluoro-methoxy) phenyl]-8-fluoro-3,4-dihydro-1H-[1,4]Piperazine also [4,3-a] benzimidazole (embodiment 132).Collect the enantiomer (RT 3.4min) of the second eluting, and by institute State fraction to evaporate to obtain (enantiomer 2) (4R or S) bromo-4-of-7-[2-(difluoro-methoxy) phenyl] the fluoro-3,4-of-8-bis- Hydrogen-1H-[1,4]Piperazine also [4,3-a] benzimidazole (embodiment 133)1H NMR(400MHz,CDCl3)δ7.42(d,J 8.9Hz,1H),7.32(m,1H),7.17(m,2H),7.05(t,J 7.6Hz,1H),6.91(d,J 5.8Hz,1H),6.61(m, 1H),5.71(t,J 3.9Hz,1H),5.02(m,2H),4.16(m,2H)。LCMS(ES+)RT 4.76min,413.0/415.0 (M+H)+。
Embodiment 134-144
Following embodiment is prepared from the precursor specified by method F.
Embodiment 145 and 146
Enantiomer 1:(4S or R) the bromo-4-of-7-[2-(difluoro-methoxy) phenyl]-8-fluoro-3,4-dihydro-1H-pyrazine And [1,2-a] benzimidazolyl-2 radicals-t-butyl formate；Enantiomer 2:(4R or S) the bromo-4-of-7-[2-(difluoro-methoxy) benzene Base]-8-fluoro-3,4-dihydro-1H-pyrazine also [1,2-a] benzimidazolyl-2 radicals-t-butyl formate
By under the conditions of SFC Chiralpak AD (50*216mm*mm, flow velocity 360mL/min, 15 DEG C, CO2+ 20%i-PrOH, the solution of the 20g/L concentration of injection 5mL) upper chirally purified embodiment 12, separate title compound.Collect head The enantiomer (RT 3.9min) of first eluting, and described fraction is evaporated to obtain enantiomer 1:(4S or R)-7-is bromo- 4-[2-(difluoro-methoxy) phenyl]-8-fluoro-3,4-dihydro-1H-pyrazine also [1,2-a] benzimidazolyl-2 radicals-t-butyl formate is (real Execute example 145).Collect the enantiomer (RT 5.9min) of the second eluting, and described fraction is evaporated to obtain enantiomer 2:(4R or S) the bromo-4-of-7-[2-(difluoro-methoxy) phenyl]-8-fluoro-3,4-dihydro-1H-pyrazine also [1,2-a] benzimidazole- 2-t-butyl formate (embodiment 146).
Embodiment 147 and 148
Enantiomer 1:7-bromo-(4S or R)-(2-(difluoro-methoxy) phenyl)-3,4-dihydrobenzo [4,5] imidazo [1,2-a] pyrazine-2 (1H)-t-butyl formate；Enantiomer 2:7-bromo-(4R)-(2-(difluoro-methoxy) phenyl)-3,4- Dihydrobenzo [4,5] imidazo [1,2-a] pyrazine-2 (1H)-t-butyl formate
By under the conditions of SFC Chiralpak IC (50*264mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%i-PrOH, the solution of the 20g/L concentration of injection 15.5mL) upper chirally purified embodiment 13, separate title compound.Collect First the enantiomer (RT6.6min) of eluting is collected, and evaporates described fraction to obtain the bromo-(4R of enantiomer 1:7- Or S)-(2-(difluoro-methoxy) phenyl)-3,4-dihydrobenzo [4,5] imidazo [1,2-a] pyrazine-2 (1H)-t-butyl formate (embodiment 147).Collect the enantiomer (RT 11.3min) of the second eluting, and by different to obtain mapping for the evaporation of described fraction Structure body 2:7-bromo-(4S)-(2-(difluoro-methoxy) phenyl)-3,4-dihydrobenzo [4,5] imidazo [1,2-a] pyrazine-2 (1H)-t-butyl formate (embodiment 148).
Embodiment 149
Enantiomer 1:1-[(4S or R)-4-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-8-(4-methyl sulphonyl benzene Base)-3,4-dihydro-1H-pyrazine also [1,2-a] benzimidazolyl-2 radicals-yl] ethyl ketone
It is sequentially added into PS-DIEA in the embodiment 136 (0.150g, 1 equivalent) solution in DCM (10mL/g) (N ° of 800280,261mg, 3.0 equivalents of Argonaut, 3.53mmol/g), chloroacetic chloride (1.2 equivalent) and N, N-diisopropyl second Amine (0.1 equivalent), and mixture is stirred at room temperature.After 20h, DIPEA (2) and chloroacetic chloride (0.5 equivalent) are added mixed Compound, is stirred at room temperature other 3h until disappearance of starting material.Then mixture is filtered, filtrate is used saturated NH4Cl Solution washing, is dried (MgSO4), concentrate in a vacuum, by column chromatography (SiO2, 0-100%EtOAc/ hexane class) and pure Change, obtain the title compound (94mg, 58%) as pale solid.LCMS(ES+)RT3.9min,530.3(M+H)+。
Embodiment 150
Enantiomer 1:(4S or R)-4-[2-(difluoro-methoxy) phenyl]-8-fluoro-2-methyl sulphonyl-7-(4-first Base sulfonvlphenyl)-3,4-dihydro-1H-pyrazine also [1,2-a] benzimidazole
It is sequentially added into PS-DIEA in the embodiment 136 (0.150g, 1 equivalent) solution in DCM (10mL/g) (N ° of 800280,261mg, 3.0 equivalents of Argonaut, 3.53mmol/g), mesyl chloride (43mg, 1.2 equivalents) and N, N-bis-are different Propylethylamine (4mg, 0.1 equivalent).Mixture is stirred at room temperature.After 20h, by DIPEA (2) and mesyl chloride, (0.5 works as Amount) add mixture, 3h is stirred at room temperature until disappearance of starting material.Then mixture is filtered, by filtrate with saturated NH4Cl solution washing, is dried (MgSO4), concentrate in a vacuum, by column chromatography (SiO2, 0-100%EtOAc/ hexane Class) purification, obtain the title compound (51mg, 29% yield) as pale solid.1H NMR(400MHz,CDCl3)δ 7.94(d,J 8.3Hz,2H),7.56(m,3H),7.41(t,J 8.1Hz,1H),7.26(d,J 6.7Hz,1H),7.13(t,J 7.5Hz,1H),6.85(d,J 8.4Hz,1H),6.67(t,J 68.2Hz,1H),6.66(d,J 18.7Hz,1H),5.97(t,J 4.1Hz,1H),5.03(d,J 16.8Hz,1H),4.78(d,J 16.6Hz,1H),4.06(dd,J 13.5Hz,J 4.2Hz, 1H),3.98(dd,J 13.7Hz,J 4.3Hz,1H),2.78(s,3H),3.07(s,3H)。LCMS(ES+)RT 4.2min, 566.3(M+H)+。
Embodiment 151
Enantiomer 1:(4S or R)-4-[2-(difluoro-methoxy) phenyl]-8-fluoro-2-methyl-7-(4-sulfonyloxy methyl Base phenyl)-3,4-dihydro-1H-pyrazine also [1,2-a] benzimidazole
Add in the embodiment 136 (0.150g, 0.308mmol) solution in MeOH (0.673g, 21.0mmol) Et3N (0.029g, 0.28mmol), formaldehyde (0.0244g, 0.301mmol) and sodium cyanoborohydride (0.02g, 0.317mmol). Reactant mixture is stirred at room temperature 14h.Reactant mixture is dissolved in EtOAc, washs with water and saline, be dried (MgSO4), and concentrate in a vacuum.By preparative TLC (eluent: the methanol solution of 90DCM/10 ammonia) purification residue, Obtain title compound (12mg, 8%).LCMS(ES+)RT 4min,502(M+H)+。
Embodiment 152 and 153
Enantiomer 1:((4S or R)-4-[2-(difluoro-methoxy) phenyl]-7-(4-methylsulfonyl phenyl)-1,2, 3,4-tetrahydrochysene pyrazine also [1,2-a] benzimidazole；Enantiomer 2 (4R or S)-4-[2-(difluoro-methoxy) phenyl]-7-(4- Methylsulfonyl phenyl)-1,2,3,4-tetrahydrochysene pyrazine also [1,2-a] benzimidazole
By under the conditions of LC Lux-Cell-4 (76*265mm*mm, flow velocity 200mL/min, 30 DEG C, EtOH 100%, the solution of the 5.7g/L concentration of injection 10mL) upper chirally purified embodiment 140, separate title compound.Collect first The enantiomer (RT 13min) of eluting, and described fraction is evaporated to obtain enantiomer 1 (embodiment 152).1H NMR(400MHz,CDCl3)δ7.92(d,J 8.4Hz,2H),7.81(d,J 8.4Hz,1H),7.60(d,J 8.4Hz,2H), 7.48(dd,J 8.4Hz,J 1.4Hz,1H),7.36(td,J 7.9Hz,J 1.2Hz,1H),7.25(d,J 6.3Hz,1H), 7.09(t,J 7.6Hz,1H),7.00(d,J 1.0Hz,1H),6.72(t,J 72.9Hz,1H),6.66(d,J 8.1Hz,1H), 5.88(t,J 4.0Hz,1H),4.44(q,J 17.4Hz,2H),3.68(dd,J 13.9Hz,J 4.6Hz,1H),3.38(dd, J13.4Hz,J 3.6Hz,1H),3.06(s,3H)。LCMS(ES+)RT 1.30min,470.0(M+H)+。
Collect the enantiomer (RT 18min) of the second eluting, and described fraction is evaporated to obtain enantiomer 2 (embodiment 153).1H NMR(400MHz,CDCl3)δ7.92(d,J 8.4Hz,2H),7.82(d,J 8.2Hz,1H),7.60(d, J 8.4Hz,2H),7.48(dd,J 8.5Hz,J 1.2Hz,1H),7.36(t,J 7.0Hz,1H),7.25(d,J 5.9Hz, 1H),7.09(t,J6.9Hz,1H),7.01(d,J 0.3Hz,1H),6.71(t,J 73.0Hz,1H),6.66(d,J7.2Hz, 1H),5.88(t,J 4.0Hz,1H),4.44(q,J 17.0Hz,2H),3.68(dd,J13.7Hz,J 4.6Hz,1H),3.38 (dd,J 13.7Hz,J 3.6Hz,1H),3.06(s,3H)。LCMS(ES+)RT 1.30min,470.0(M+H)+。
Embodiment 154
(the bromo-6-of 7-fluoro-1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-base) acetas
According to the method described about embodiment 116 from 1-(the bromo-4-of 5-fluoro-2-nitro-phenyl)-2-phenyl-pyrrolidin Prepare title compound (as the mixture of 2 kinds of diastereomers).LCMS(ES+) RT4.85 and 4.90min, 389.1/ 391.1(M+H)+。
Embodiment 155
The bromo-6-of 7-fluoro-1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
According to the method described about embodiment 117, the title compound prepared as water white oil from embodiment 154 (is made It is the mixture of 2 kinds of diastereomer 67/33 trans/cis) (89%).Described compound is used for without further purification Next step.1H NMR(400MHz,CDCl3)δ7.51(m,1H),7.40(m,4H),7.18(m,2H),7.00(m,1H),5.69 (t,J 6.8Hz,1H),5.53(m,1H),3.19(m,1H),2.91(m,1H),LCMS(ES+) RT 4.82 and 4.76min, 347.1/349.1(M+H)+。
Embodiment 156
The bromo-6-of 7-fluoro-1-phenyl-1,2-pyrrolin also [1,2-a] benzimidazole-3-ketone
By MnO2(1.06g, 12.2mmol) adds embodiment 155 (0.507g, 1.46mmol) at CHCl3(20mL) in In solution, and mixture is heated 5h at 60 DEG C.Add MnO2(405mg) and CHCl3(20mL), and by mixture heat additionally 2h.Residue is cooled to room temperature, bed of diatomaceous earth filters, and by solid washed with DCM.By filtrate water (2 × 50mL), Saturated NaHCO3Aqueous solution (2 × 50mL), saturated NH4Cl solution (2 × 50mL) washs, and is dried (MgSO4), concentrate in a vacuum Obtain title compound (370mg, 74%), it is used for next step without any purification.LCMS(ES+)RT 4.67min, 345/347(M+H)+。
Embodiment 157
The bromo-6-of 7-fluoro-1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
3-sec-butyl lithium borohydride (1M, 1.7mL, 1.5 equivalent) is added dropwise over cold (-78 DEG C) embodiment 156 In (307mg, 1.1mmol) solution in THF (10mL).The mixture stirring 2h that will obtain, then makes solution reach 0 DEG C. After keeping 0.5h at 0 DEG C, add MeOH (2mL).After 20min, add NaOH aqueous solution (3mL), be subsequently added water (50mL), and will obtain mixture EtOAc (100mL) extraction.Organic layer use water (50mL) washing that will merge, uses saline (2 × 50mL) washs, and is dried (MgSO4) and concentrate in a vacuum.By column chromatography (SiO2, the ammonia of 0-10% is in methanol Solution/EtOAc) purification residue, obtain mixture as 2 kinds of cis diastereomers title compound (270mg, 72%).LCMS(ES+)RT 4.27min,347.08/349.07(M+H)+。
Embodiment 158 and 159
The fluoro-7-of diastereomer 1 (1S or R, 3S or R)-6-[6-(methyl sulphonyl) pyridin-3-yl]-1-phenyl-2, 3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol；Diastereomer 2 (1R or S, 3R or S)-6-fluoro-7-[6-(first Base sulfonyl) pyridin-3-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
By under the conditions of SFC Chiralcel OD (50*266mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%MeOH, the solution of the 3.6g/L concentration of injection 17mL) upper chirally purified, separate title compound.Collect first eluting Enantiomer (RT 8.9min), and described fraction is evaporated to obtain the title compound as pale solid, diastereomeric Isomer 1 (embodiment 158) (36mg, 11%).1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.10(m,1H),7.99 (m,1H),7.62(m,1H),7.39(m,6H),6.85(s,1H),5.59(m,1H),5.46(m,1H),3.61(m,1H),3.24 (s,3H),2.75(m,1H)。LCMS(ES+)RT1.24min,424.0(M+H)+.Collect the enantiomer (RT of the second eluting 12.9min), obtain the second enantiomer diastereomer 2 (embodiment 159) as white solid (6mg, 11%).1H NMR(400MHz,CDCl3)δ8.68(d,J 0.5Hz,1H),8.10(d,J 8.6Hz,1H),7.99(m,1H), 7.40(m,7H),6.87(m,1H),5.58(m,1H),5.46(m,1H),3.61(m,1H),3.24(s,3H),2.75(m,1H)。 LCMS(ES+)RT 1.24min,424.0(M+H)+。
Embodiment 160
Diastereomer 1 [the bromo-1-of (1R or S, 3R or S)-7-[2-(difluoro-methoxy) phenyl] the fluoro-2,3-of-6-bis- Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-base] acetas
By under the conditions of LC Chiralpak AD (100*500mm*mm, flow velocity 300mL/min, 30 DEG C, heptane- I-PrOH (1:1), the solution of the 25g/L concentration of injection 10mL) upper chirally purified, implemented by 4 kinds of diastereomers of purification Example 116 separates title intermediate.First the peak (RT 13min) of eluting contains 2 kinds of diastereomers (1R or S, 3R or S) (1S or R, 3R or S).Second peak (RT 22min) contains the third diastereomer (1R or S, 3S or R), and the 3rd Individual peak (RT 30min) contains the 4th kind of diastereomer (1S or R, 3S or R).
By under the conditions of LC Lux-Cell-4 (78*265mm*mm, flow velocity 200mL/min, 30 DEG C, heptane-i- PrOH (7:3), the solution of the 100g/L concentration of injection 2.5mL) upper chirally purified, separate 2 kinds of diastereomers (1R or S, 3R Or S) and the mixture of (1S or R, 3R or S).Collect the enantiomer (RT 9min) of first eluting, and described fraction is steamed Send out to obtain the title compound as colourless foam.Collect the enantiomer (RT 12min) of the second eluting, and by described Fraction concentrates to obtain diastereomer (1S or R, 1R or S) in a vacuum.1H NMRδ:7.75(d,J 9.6Hz,1H), 7.45(m,1H),7.33(m,3H),7.21(t,J 7.6Hz,1H),6.86(d,J 7.0Hz,1H),6.23(dd,J 7.9Hz,J 3.6Hz,1H),5.92(dd,J 8.2Hz,J 4.3Hz,1H),3.66(m,1H),2.41(dt,J 14.3Hz,J 4.0Hz, 1H),2.03(s,3H)。
Embodiment 161
Diastereomer 1:(1R or S, 3R or S) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl] the fluoro-2,3-of-6-bis- Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
By K2CO3(172mg, 1 equivalent) adds the embodiment 160 (743mg, 1.72mmol) solution in MeOH (5.2mL) In.The mixture obtained is stirred at room temperature 4h.Mixture is filtered, evaporation, and the residue obtained is dissolved in EtOAc In, wash with saline (1 ×), be dried (MgSO4) and concentrate in a vacuum, obtain the title intermediate as pale solid (710mg, 89%).LCMS(ES+)RT 1.50min,413.0/415.0(M+H)+。
Embodiment 162
Diastereomer 1:(1R or S, 3R or S) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-6-fluoro-3-methoxy Base-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
Sodium hydride (50mg is dispersed in mineral oil, 1.25mmol, 80%w/w) is added portionwise into embodiment 161 In (413mg, 1.0mmol) solution in anhydrous THF (5mL).By mixture sonication 5min, then it is stirred at room temperature 30min.Add iodomethane (287mg, 2mmol), and reactant mixture is stirred 2h at 0 DEG C, 18h is then stirred at room temperature.Logical Cross column chromatography (SiO2, 0-45%EtOAc/ heptane) and purification, obtain the title intermediate (350mg, 82%) as water white oil. LCMS(ES+)RT 5.24min,427.0/429.0(M+H)+。
Embodiment 163
Diastereomer 4 [the bromo-1-of (1S or R, 3S or R)-7-[2-(difluoro-methoxy) phenyl] the fluoro-2,3-of-6-bis- Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-base] acetas
By the mixture of 4 kinds of diastereomers of purification embodiment 116 described in the embodiment 160, separate mark Topic intermediate is as the 4th kind of diastereomer (RT 30min).1H NMR(DMSO-d6)δ:7.75(d,J 9.6Hz,1H), 7.45(m,1H),7.33(m,3H),7.21(t,J 7.6Hz,1H),6.86(d,J 7.6Hz,1H),6.23(dd,J 7.9Hz,J 3.6Hz,1H),5.92(dd,J 8.3Hz,J 4.3Hz,1H),3.66(m,1H),2.41(dt,J 14.3Hz,J 3.9Hz, 1H),2.03(s,3H)。
Embodiment 164
Diastereomer 4:(1S or R, 3S or R) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl] the fluoro-2,3-of-6-bis- Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
By K2CO3(172mg, 1 equivalent) adds the embodiment 163 (430mg, 0.95mmol) solution in MeOH (3.0mL) In.The mixture obtained is stirred at room temperature 4h.Mixture is filtered, concentrates in a vacuum, and the residue obtained is dissolved In EtOAc, wash with saline (1 ×), be dried (MgSO4) and concentrate in a vacuum, obtain the title as pale solid Compound (346mg, 88%).LCMS(ES+)RT 4.62min,413.1/415.1(M+H)+。
Embodiment 165
Diastereomer 4:(1S or R, 3S or R) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl]-6-fluoro-3-methoxy Base-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
Sodium hydride (50mg is dispersed in mineral oil, 1.25mmol, 80%w/w) is added portionwise into embodiment 164 In (348mg, 0.84mmol) solution in anhydrous THF (4.2mL).By mixture sonication 5min, then it is stirred at room temperature 30min.Add iodomethane (241mg, 1.68mmol), and reactant mixture is stirred 2h at 0 DEG C, 18h is then stirred at room temperature. By column chromatography (SiO2, 0-40%EtOAc/ heptane) purification, obtain title intermediate as water white oil (290mg, 80%).LCMS(ES+)RT 5.24min,427.1/429.1(M+H)+。
Embodiment 166
Diastereomer 4:2-(5-{ (1S or R, 3S or R)-1-[2-(difluoro-methoxy) phenyl]-6-fluoro-3-methoxy Base-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-7-base } pyridine-2-base) propane-2-alcohol
By HCl, (4N is at 1,4-bis-Solution in alkane, 0.2mL) add embodiment 78 (25mg, 0.045mmol) at DCM (0.5mL) in the solution in, and mixture is stirred at room temperature 1h.Solvent is concentrated in a vacuum, and by residue at Et2O Middle grinding.Being collected by filtration by the powder obtained, and concentrate in a vacuum, obtain as light orange powder is titled Compound (5mg, 23%).1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.48(d,J 8.1Hz,1H),8.12(d,J 8.4Hz,1H),7.84(d,J 11.4Hz,1H),7.36(m,6H),6.82(d,J 7.5Hz,1H),5.96(dd,J 8.3Hz,J 3.4Hz,1H),5.04(dd,J 7.4Hz,J22.6Hz,1H),3.58(m,4H),2.42(m,1H),1.59(s,6H)。LCMS (ES+)RT1.45min,484.0(M+H)+。
Embodiment 167
Diastereomer 1:2-(5-{ (1R or S, 3R or S)-1-[2-(difluoro-methoxy) phenyl]-6-fluoro-3-methoxy Base-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-7-base } pyridine-2-base) propane-2-alcohol
By HCl, (4N is at 1,4-bis-Solution in alkane, 0.5mL) add embodiment 79 (168mg) in DCM (0.5mL) Solution in, and by mixture 0 DEG C stir 3h.Solvent is concentrated in a vacuum, and by residue at Et2O grinds, then EtOAc grinds.The powder obtained is collected by filtration, and concentrates in a vacuum, obtain as pale powder Title compound (135mg, 100%).1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.48(d,J 8.1Hz, 1H),8.12(d,J 8.4Hz,1H),7.84(d,J 11.4Hz,1H),7.36(m,6H),6.82(d,J 7.5Hz,1H),5.96 (dd,J 8.3Hz,J 3.4Hz,1H),5.04(dd,J 7.4Hz,J22.6Hz,1H),3.58(m,4H),2.42(m,1H), 1.59(s,6H)。LCMS(ES+)RT 1.45min,484.0(M+H)+。
Embodiment 168
The bromo-1-of (1R or S)-7-[2-(difluoro-methoxy) phenyl]-3,6-two fluoro-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole
The solution being dissolved in DCM (2.5mL) from intermediate 161 (200mg, 1.0 equivalents) prepares title compound.0 DEG C, add the diethylaminosulfur trifluoride (1.2 equivalent) solution in 0.5mL DCM.Mixture is stirred 30min at 0 DEG C. Reactant mixture is used saturated NaHCO3Aqueous solution quencher, extracts with DCM, is dried (MgSO4) and concentrate in a vacuum.By remnants Thing passes through column chromatography (SiO2, 0-6%MeOH/DCM) and purification, the preparative reverse-phase chromatography purification instructed by UV subsequently, Obtain the title compound (102mg, 51%) as beige solid glass.LCMS(ES+)RT1.60min,415.0/417.0(M +H)+。
Embodiment 169
Enantiomer 2:2-(5-{ (1R or S)-1-[2-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrole Cough up also [1,2-a] benzimidazole-7-base } pyridine-2-base) propane-2-alcohol hydrochloride
At 0 DEG C, 4N HCl (0.5mL) is added in the embodiment 78 (0.38g, 0.75mmol) solution in DCM (5mL). Reactant is stirred at room temperature 30min.Reactant mixture is concentrated in a vacuum and and EtOAc/iPr2O (1:1,2mL) is together Grind, obtain the title compound (355mg, 96%) as cream-coloured powder.LCMS(ES+)RT 1.45min,454.0(M+H)+。
Embodiment 170 and 171
Diastereomer 1:(1R or S, 3R or S) the bromo-1-of-7-[2-(difluoro-methoxy) phenyl] the fluoro-2,3-of-3,6-two Dihydro-1H-pyrrolo-[1,2-a] benzimidazole；Diastereomer 2:(1R or S, 3S or R)-7-bromo-1-[2-(difluoromethoxy Base) phenyl]-3,6-two fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
By under the conditions of SFC Whelko-O1 (R, R) (50*227mm*mm, flow velocity 360mL/min, 25 DEG C, CO2+ 20%i-PrOH, the solution 11.6g/L of the concentration of injection 22.5mL) upper chirally purified, (non-by chirally purified embodiment 168 Enantiomer ratio 60/40) obtain title compound.Collect the diastereomer (RT 4.9min) of first eluting, and will Described fraction evaporates to obtain title compound, diastereomer 1 (embodiment 170) (96mg, 19%).Collect the second eluting Diastereomer (RT 7.9min), and by described fraction evaporate to obtain other diastereomer, diastereomer 2 (embodiment 171) (154mg, 31%).
Embodiment 172
(1R or S, 3R or S)-3-bromo-1-of azido-7-[2-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H- Pyrrolo-[1,2-a] benzimidazole
In the intermediate 108 (0.1g, 1.0 equivalents) solution in toluene (0.5mL), it is added dropwise over diphenylphosphine at 0 DEG C Acyl azide (1.3 equivalent), is subsequently added 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (1.4 equivalent).Will be anti- Mixture is answered at 0 DEG C of stirring 1h and 16h to be stirred at room temperature.Reactant mixture is dissolved in EtOAc, and washes with water.To have Machine is dried (Na mutually2SO4) and concentrate in a vacuum, obtain 110mg (100%) orange oil, it is used for without further purification Next step.LCMS(ES+)RT 5.20min,438.0/440.0(M+H)+。
Embodiment 173
The bromo-1-of (1R or S, 3R or S)-7-[2-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1, 2-a] benzimidazole-3-amine
Embodiment 172 (0.110g, 1.1 equivalents) is dissolved in 1mL toluene.Add triphenylphosphine (3 equivalent) and 0.5mL Water, and reactant mixture is stirred at room temperature 16h.Mixture is concentrated in a vacuum and is dissolved in EtOAc, and with 1N's HCl extracts.By aqueous phase NaHCO3Neutralize, extract with DCM, be dried (Na2SO4) and concentrate in a vacuum, obtain title compound (87,84%).LCMS(ES+)RT 3.51min,412.0/414.0(M+H)+。
Embodiment 174 (method G)
1-(5-{1-[2-(difluoro-methoxy) phenyl]-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole- 7-yl } pyrimidine-2-base)-4-methyl piperidine-4-formic acid
Embodiment 94 (0.384g, 0.679mmol) is dissolved in THF (8mL) and 2mL water.Add Lithium hydrate one water Compound (0.102g, 1.36mmol), and reactant is heated to 70 DEG C of holding 18h.Reactant is concentrated in a vacuum, and by residual Excess is dissolved in the THF of minimum and dilute with water.By mixture EtOAc process, and organic layer is extracted.By aqueous solution Dropwise process to pH7 with AcOH, and by solution stirring.Precipitate is leached and is dried in a vacuum.Pure by preparation HPLC Change solid, obtain as emulsifiable paste shape solid title compound (0.084g, 23%).1H NMR(300MHz,DMSO-d6)δ:8.38 (d,J 1.7Hz,2H),7.55(m,1H),7.41(m,1H),7.31(m,2H),7.18(td,J 7.6Hz,J 0.9Hz,1H), 6.98(d,J 7.1Hz,1H),6.85(dd,J 7.7Hz,J 1.4Hz,1H),5.88(m,1H),4.24(m,2H),3.15(m, 6H),1.97(m,2H),1.34(m,2H),1.16(s,3H)。LCMS(ES+)RT 1.57min,538.0(M+H)+。
Embodiment 175
1-(5-{3-[2-(difluoro-methoxy) phenyl]-7-fluoro-2,3-dihydro-1H-imidazo [1,2-a] benzimidazole- 6-yl } pyrimidine-2-base)-4-methyl piperidine-4-formic acid
By method G, from embodiment 100 (0.21g, 0.36mmol) and lithium hydroxide monohydrate (0.055g, 0.74mmol) prepare title compound (0.041g, 21%).1H NMR(DMSO-d6,300MHz)δ:8.36(d,J 1.6Hz, 2H),7.42(m,2H),7.31(m,2H),7.21(td,J 7.7Hz,J 1.0Hz,1H),7.14(d,J 11.8Hz,1H), 6.96(dd,J 7.8Hz,J 1.5Hz,1H),6.78(d,J 7.1Hz,1H),5.89(dd,J 8.8Hz,J 4.8Hz,1H), 4.47(t,J 9.6Hz,1H),4.22(m,1H),3.76(dd,J 9.8Hz,2 5.2Hz,1H),3.26(m,4H),1.98(m, 2H),1.27(m,2H),1.11(s,2H)。LCMS(ES+)RT 1.96min,539.8(M+H)+。
Embodiment 176
(1S, 5R)-3-[5-[1-1-[2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H-imidazo [1,2-a] benzo Imidazoles-7-base] pyrimidine-2-base]-3-azabicyclo [3.2.1] octane-8-formic acid
By method G, from embodiment 101 (0.197g, 0.36mmol) and lithium hydroxide monohydrate (0.108g, 1.44mmol) prepare title compound (0.077g, 40%).1H NMR(DMSO-d6)δ:8.48(s,2H),7.39(m,2H), 7.29(m,3H),7.19(m,2H),6.95(m,2H),5.90(dd,J18.8Hz,J24.7Hz,1H),4.47(t,J 9.3Hz, 1H),4.37(d,J 12.3Hz,2H),3.75(dd,J19.7Hz,J24.9Hz,1H),2.96(d,J 12.0Hz,2H),2.57 (s,3H),1.67(m,2H),1.35(d,J 7.5Hz,2H)。LCMS(ES+)RT 1.55min,533.8(M+H)+。
Embodiment 177
Enantiomer 2:(1S, 5R)-3-[5-[(1R or S)-1-[2-(difluoro-methoxy) phenyl]-2,3-dihydro-1H- Pyrrolo-[1,2-a] benzimidazole-7-base] pyrimidine-2-base]-3-azabicyclo [3.2.1] octane-8-formic acid
By method G, from embodiment 102 (0.163g, 0.30mmol) and lithium hydroxide monohydrate (0.089g, 1.19mmol) prepare title compound (0.083g, 52%).1H NMR(DMSO-d6)δ:12.29(m,1H),8.50(s,2H), 7.65(d,J 8.4Hz,1H),7.40(m,3H),7.31(m,1H),7.18(m,1H),7.10(s,1H),6.85(d,J 7.6Hz,1H),5.89(m,1H),4.40(d,J 12.4Hz,2H),3.14(m,3H),2.99(m,2H),2.62(d,J 25.7Hz,3H),1.68(m,2H),1.37(d,J 8.2Hz,2H)。LCMS(ES+)RT 1.20min,532.2(M+H)+。
Embodiment 178
Enantiomer 1:(1S, 5R)-3-[5-[(4S or R)-2-tert-butoxycarbonyl-4-[2-(difluoro-methoxy) benzene Base]-8-fluoro-3,4-dihydro-1H-pyrazine also [1,2-a] benzimidazole-7-base] pyrimidine-2-base]-3-azabicyclo [3.2.1] Octane-8-formic acid
By the embodiment 99 (100mg, 0.15mmol) solution in THF (3mL) with NaOH (10%w/v aqueous solution, 286uL) process with water (1mL), and be heated to 70 DEG C of holding 9h, be then cooled to room temperature.By reactant mixture EtOAc (25mL) dilution, is acidified by adding AcOH (2mL), and washs with water (25mL).By aqueous layer with EtOAc (25mL) Extraction, and the organic extract water (25mL) merged and saline (25mL) are washed and is dried (MgSO4), and the denseest Contracting, obtains colorless gum.LCMS(ES+)RT 1.30min,665.0(M+H)+。
Embodiment 179
Enantiomer 1:(1S, 5R)-3-[5-[(4S or R)-4-[2-(difluoro-methoxy) phenyl]-8-fluoro-1,2,3, 4-tetrahydrochysene pyrazine also [1,2-a] benzimidazole-7-base] pyrimidine-2-base]-3-azabicyclo [3.2.1] octane-8-formic acid disalt Hydrochlorate
Embodiment 178 (200mg, 0.30mmol) is dissolved in the HCl of 4M at 1,4-bis-In solution (4mL) in alkane And 1.5h is stirred at room temperature.By reactant mixture 1,4-bis-Alkane (10mL) dilute, concentrate in a vacuum, be suspended in Isosorbide-5-Nitrae- TwoIn alkane (25mL) and concentrate in a vacuum.By thick residue at i-Pr2O grinds, obtains the title as yellow solid Compound (94mg) (100%).δH(400MHz,DMSO-d6)10.2(brs,1H),8.20(s,2H),7.63(d,J 11.2Hz, 1H),7.56(m,1H),7.40(d,1H),7.38(tr,J 74.4Hz,1H),7.27(m,2H),6.49(d,J 6.9Hz,1H), 6.12(dd,J 9.6,4.9Hz,1H),4.75(s,2H),4.37(dd,J 12.9,3.3Hz,2H),4.03(m,1H),3.70- 3.57(m,2H),3.00(d,J 11.9Hz,2H),2.65(s,1H),2.58(s,2H),1.68(m,2H),1.37(d,J 7.8Hz,2H),1.04(d,J 6.1Hz,2H)。LCMS(ES+)RT 0.90min,565.0(M+H)+。
Embodiment 180-186
Using suitable borate or boric acid, using method C is (that be obtained commercially or above intermediate from the precursor specified Preparation) prepare following embodiment.
Embodiment 187 method H
2-(5-{ (1R)-1-[2-(difluoro-methoxy) phenyl]-8-fluoro-3-hydroxyl-2,3-dihydro-1H-pyrrolo-[1,2- A] benzimidazole-7-base } pyrimidine-2-base)-2-methyl propionitrile
By 2-(5-Bromopyrimidine-2-base)-2-methyl-propanenitrile (170mg, 0.75mmol), double valeryl two boron (0.235g, 0.927mmol), potassium acetate (0.153g, 1.545mmol) is suspended in anhydrous the two of 5mL degassingIn alkane, be subsequently adding [1, Double (diphenylphosphino) ferrocene of 1'-] palladium chloride (II) (0.028g, 0.039mmol).Reactant mixture is deaerated other 5 Minute, and heat 1 hour at 105 DEG C.Reactant is cooled to room temperature, and add intermediate 110 (0.200g, 0.484mmol), Cesium carbonate (0.187g, 0.968mmol), water (0.315mL), and mixture is heated 18h at 100 DEG C.By reactant mixture warp Na2SO4Filter with 45 μMs of filters, wash with EtOAc, and concentrate in a vacuum.By chromatography (SiO2, 80%EtOAc/5% MeOH solution in hexane) purification residue, obtain the title compound (175mg, 75%) as brown solid.LCMS (ES+)RT 4.39min,480.2(M+H)+。
Embodiment 188
(1R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-8-[2-(4-fluorine tetrahydrochysene-2H-pyrans-4-base) pyrimidine-5- Base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
Use intermediate 114 (200mg, 0.766mmol) and intermediate 110 to prepare title compound according to method H, obtain Compound (108mg, 43%) as brown solid.LCMS(ES+)RT4.15min,515.3(M+H)+。
Embodiment 189
(1R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-8-[2-(3-fluorine oxetanes-3-base) pyrimidine-5- Base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
Intermediate 135 (180mg, 0.77mmol) and intermediate 110 is used to prepare title compound according to method H.LCMS (ES+)RT 1.32min,487.2(M+H)+。
Embodiment 191
3-(difluoro-methoxy)-2-[(1R, 3S)-6-fluoro-3-hydroxyl-7-[2-(1-hydroxyl-1-methyl-ethyl) pyrimidine- 5-yl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-1-base] butyl benzoate
Under the CO gas of 4 atmospheric pressure by embodiment 182 (900mg, 1.783mmol), sodium carbonate (944mg, 8.913mmol), dichloro [double (dicyclohexyl phosphino-) propane] palladium (II) (54.7mg, 0.08913mmol) is at 10mL n-butyl alcohol In solution 150 DEG C heat 16h.Reactant mixture is concentrated in a vacuum, residue is dissolved in 50mL EtOAc, and Wash 3 times with the NaOH of 20mL 0.1M.Organic layer is dried through anhydrous sodium sulfate and concentrates in a vacuum.Crude material is led to Cross chromatography (SiO2, the EtOAc of 80% solution in hexane) and purification, obtain title compound (490mg, 48.2%). LCMS(ES+)RT 2.66min。571.25(M+H)+。
Embodiment 192
(1R, 3R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-[2-(4-fluorine tetrahydropyran-4-base) pyrimidine-5- Base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
Intermediate 114 (0.50g, 1.92mmol) and embodiment 161 (0.300g, 0.75mmol) system is used according to method H Standby title compound, obtains compound (195mg, 52%).LCMS(ES+)RT1.39min,515.0(M+H)+。
Embodiment 193
(1R) [2-(4-fluorine tetrahydrochysene-2H-pyrans-4-base) is phonetic for-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-3,6-two Pyridine-5-base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
Embodiment 192 (0.050g, 0.097mmol) and DAST (0.017mL, 0.117mmol) is used to prepare according to method I Title compound, obtains the title compound (20mg, 42%) as white solid.LCMS(ES+)RT 1.45min。517.0 (M+H)+。
Embodiment 194
(1R, 3R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-[2-(3-fluorine oxetanes-3-base) pyrimidine-5- Base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
By method H, prepare title compound from embodiment 161 and intermediate 135.LCMS(ES+)RT 1.36min, 487.0(M+H)+。
Embodiment 195
(1R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-3,6-two [2-(3-fluorine oxetanes-3-base) pyrimidine- 5-yl]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
Embodiment 194 (0.170g, 0.350mmol) and DAST (0.061mL, 0.419mmol) is used to prepare according to method I Title compound, obtains the title compound (102mg, 62%) as white solid.LCMS(ES+)RT 1.46min,489.0 (M+H)+。
Embodiment 196 and 197
(1R, 3R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-3,6-two [2-(3-fluorine oxetanes-3-base) Pyrimidine-5-base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole and (1R, 3S or R)-1-[2-(difluoro-methoxy) benzene Base] the fluoro-7-of-3,6-two [2-(3-fluorine oxetanes-3-base) pyrimidine-5-base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles
Title compound is prepared from embodiment 170 and embodiment 171 respectively by method H intermediate 135.LCMS(ES+)RT 1.46min,489.0(M+H)+。
Embodiment 198
(1R, 3R)-1-[2-(difluoro-methoxy) phenyl]-7-[2-(3-fluorine oxetanes-3-base) pyrimidine-5-base]- 2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
By method H, prepare title compound from intermediate 148 and intermediate 135.LCMS(ES+)RT 1.33min, 469.0(M+H)+。
Embodiment 199
(1R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-3-[2-(3-fluorine oxetanes-3-base) pyrimidine-5- Base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
Embodiment 198 (00.170g, 0.363mmol) and DAST (0.06mL, 0.43mmol) is used to prepare according to method I Title compound, obtains the title compound (50mg, 29%) as white solid.LCMS(ES+)RT 1.39min,471.0 (M+H)+。
Embodiment 200 and 201
[2-(3-fluorine oxetanes-3-base) is phonetic for (1R, 3R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-3- Pyridine-5-base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole and (1R, 3S or R)-1-[2-(difluoro-methoxy) benzene Base] the fluoro-7-of-3-[2-(3-fluorine oxetanes-3-base) pyrimidine-5-base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzo miaow Azoles
Title compound is prepared from intermediate 111 and 112 respectively by method H intermediate 135.LCMS(ES+)RT 1.40min,471.0(M+H)+。
Embodiment 202
2-(5-{ (1R, 3R)-1-[2-(difluoro-methoxy) phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles-7-base pyrimidine-2-base)-2-methyl propionitrile
According to method H use intermediate 111 (0.068g, 0.30216mmol) and 2-(5-Bromopyrimidine-2-base)-2-methyl- Title compound (0.108g, 92%) prepared by propionitrile.LCMS(ES+)RT 1.55min,464.0(M+H)+。
Embodiment 203
(1R, 3R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-3-[2-(4-fluorine tetrahydropyran-4-base) pyrimidine-5- Base]-2,3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
Intermediate 111 (122mg, 0.30mmol) and intermediate 114 (100mg, 0.38mmol) is used to prepare according to method H Title compound (0.025g, 13%).LCMS(ES+)RT 1.47min,499.0(M+H)+。
Embodiment 204
3-[5-[(1R, 3R)-1-[2-(difluoro-methoxy) phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles-7-base] pyrimidine-2-base] oxetanes-3-alcohol
Intermediate 111 (100mg, 0.25mmol) and intermediate 133 (116mg, 0.50mmol) is used to prepare according to method H Title compound, obtains brown solid (0.072g, 61%).LCMS(ES+)RT 1.32min,469.0(M+H)+。
Embodiment 205
(1R)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-6-[6-(1-fluoro-1-methyl-ethyl)-3-pyridine radicals]-2, 3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole
Title compound is prepared from embodiment 169 (0.315g, 0.695mmol) and DAST (1.39mmol) according to method I, Obtain white solid (0.220g, 66%).LCMS(ES+)RT 1.64min,456.0(M+H)+。
Embodiment 206
9-[5-[(1R, 3R)-1-[2-(difluoro-methoxy) phenyl]-3-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a] benzene And imidazoles-7-base] pyrimidine-2-base]-3,7-dioxa-9-azabicyclo [3.3.1] nonane
Intermediate 111 (216mg, 0.54mmol) and intermediate 140 (195mg, 0.68mmol) is used to prepare according to method H Title compound, obtains brown solid (0.206g, 58%).LCMS(ES+)RT 1.43min,524.0(M+H)+。
Embodiment 207
3-(difluoro-methoxy)-2-{ (1R, 3R)-3-hydroxyl-7-[2-(2-hydroxy propane-2-base) pyrimidine-5-base]-2, 3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-1-base } benzonitrile
Embodiment 181 (180mg, 0.37mmol) and zinc cyanide (87mg, 0.74mmol) are dissolved in dry DMF (3mL) In.Add tetrakis triphenylphosphine palladium (0) (43.2mg, 0.037mmol), and by mixture under microwave radiation 180 DEG C of heating 30 minutes.Reactant mixture is poured on ice, adds saturated NaHCO3Solution, and by reactant mixture with EtOAc (3 × 10mL) Extract with the mixture (3 × 10mL) of DCM/MeOH (9:1).By the organic layer of merging through MgSO4It is dried and concentrates in a vacuum. By rough compound by chromatography (SiO2, the MeOH of 0.5-1% solution in DCM) and purification and at Et2Recrystallization in O, Obtain the title compound (76mg, 43%) as white solid.LCMS(ES+)RT 1.22min,478.0(M+H)+。
Embodiment 208
3-(difluoro-methoxy)-2-{ (1R, 3S)-3-hydroxyl-7-[2-(2-hydroxy propane-2-base) pyrimidine-5-base]-2, 3-dihydro-1H-pyrrolo-[1,2-a] benzimidazole-1-base } benzonitrile
By with embodiment 210 prepare similar operation, from embodiment 182 (150mg, 0.308mmol), zinc cyanide (73mg, 0.62mmol), DMF (2mL) and tetrakis triphenylphosphine palladium (0) (36mg, 0.031mmol) prepare title compound (14mg, 9.5%).LCMS(ES+)RT 1.76min,478.0(M+H)+。
Embodiment 209 and 210-method J
(1R, 3R)-1-(5-chloro-2-(difluoro-methoxy) phenyl)-7-(4-((R or S)-S-methyl sulfur sulfoximide base (sulfonimidoyl)) phenyl)-2,3-dihydro-1H-benzo [d] pyrrolo-[1,2-a] imidazoles-3-alcohol and (1R, 3R)-1- (5-chloro-2-(difluoro-methoxy) phenyl)-7-(4-((S or R)-S-methyl sulfur sulfoximide base) phenyl)-2,3-dihydro-1H-benzene And [d] pyrrolo-[1,2-a] imidazoles-3-alcohol
To intermediate 161 (250mg, 0.58mmol) in the two of degassingIn mixture in alkane (4mL), add middle Body 143 (164mg, 0.58mmol), Na2CO3(123mg, 1.16mmol) and water (1mL), and by mixture argon cleaning.Add Enter Pd2(dba)3(11mg, 0.12mmol) and Tetrafluoroboric acid (17mg, 0.58mmol), and by mixture at microwave equipment (Biotage Initiator) stirs 15 minutes at 100 DEG C.By reactant mixture at NaCl solution (3mL) and EtOAc (4mL) distribute between.Organic facies is separated, through Na2SO4It is dried and concentrates in a vacuum.By chromatography (SiO2, 5% MeOH solution in DCM) and pass through preparation HPLC at SiO2(Prep-C18) upper water/MeCN is as eluent (gradient 30/70 until 70/30) purification residue.Concentrate in a vacuum and after lyophilization, obtain as 2 kinds of diastereomers The expectation product (147mg, 50%) of mixture, passed through chiral chromatography (Chiracel OJ-H, 250 × 30mm, 5 μ M, eluent: heptane/EtOH/MeOH, 2/1/1, flow velocity=30ml/min) separate.Collect the isomer of first eluting (8.4min) and by described fraction evaporate to obtain embodiment 209 (57mg, 19.4%).1H NMR(400MHz,DMSO-d6)δ ppm 7.95(d,J 8.4Hz,2H),7.80(d,J 8.4Hz,1H),7.77(d,J 8.4Hz,2H),7.60(dd,J 8.4, 1.77Hz,1H),7.48(dd,J 8.8,2.7Hz,1H),7.44(t,J 73.4Hz,1H),7.38(m,2H),7.01(d,J 2.6Hz,1H),6.13(d,J 5.5Hz,1H),5.88(dd,J 8.4,4.0Hz,1H),5.23(m,1H),4.19(s,1H), 3.50(m,1H),3.07(s,3H),2.34(m,1H)。LCMS(ES+)RT 1.39min,504.14(M+H)+
Collect the second eluting isomer (13.9min) and by the evaporation of described fraction with obtain embodiment 210 (56mg, 19%).LCMS(ES+)RT 1.39min,504.14(M+H)+。
There is no distribution absolute configuration at sulfur sulfoximide residue.
Embodiment 211 and 212
(1R, 3R)-1-(2-(difluoro-methoxy) phenyl)-7-(4-((R or S)-S-methyl sulfur sulfoximide base) phenyl)-2, 3-dihydro-1-H-benzo [d] pyrrolo-[1,2-a] imidazoles-3-alcohol and (1R, 3R)-1-(2-(difluoro-methoxy) phenyl)-7- (4-((S or R)-S-methyl sulfur sulfoximide base) phenyl)-2,3-dihydro-1-H-benzo [d] pyrrolo-[1,2-a] imidazoles-3-alcohol
As described in embodiment 212 and 213 from intermediate 148 (500mg, 1.27mmol) and 4,4,5,5-tetramethyl- 2-(4-(S-methyl sulfur sulfoximide base) phenyl)-1,3,2-dioxaborolan alkane (356mg, 1.27mmol) prepares titled Compound, obtains the 330mg (55.6%) mixture as 2 kinds of diastereomers, is passed through chromatography (Chiralpak AY, 230 × 100mm, 20 μm, eluent: heptane/ethanol 1/1, flow velocity=400ml/min) separate.Collect the different of first eluting Described fraction is also evaporated to obtain embodiment 211 (146mg, 24%) by structure body (9.6min).1H NMR(400MHz,DMSO- d6)δppm 7.93(d,J 8.4Hz,2H),7.78(d,J 8.4Hz,1H),7.72(d,J 8.4Hz,2H),7.56(dd,J 8.4,1.7Hz,1H),7.41(t,J 73.7Hz,1H),7.40(m,1H),7.33(d,J 7.8Hz,1H),7.24(m,1H), 7.18(dd,J 7.8,1.0Hz,1H),7.00(dd,J 7.8,1.3Hz,1H),6.09(d,J 5.5Hz,1H),5.88(dd,J 8.2,4.8Hz,1H),5.25(m,1H),4.18(s,1H),3.49(m,1H),3.07(s,3H),2.31(m,1H)。LCMS(ES+)RT 1.28min,470.22(M+H)+。
Collect the isomer (12.9min) of the second eluting, described fraction is evaporated, and residue is passed through chromatography (SiO2, the MeOH of 5% solution in DCM) it is further purified, obtain embodiment 212 (115mg, 19%).LCMS(ES+)RT 1.28min,470.17(M+H)+。
There is no distribution absolute configuration at sulfur sulfoximide residue.
Embodiment 213-235
Using suitable borate or boric acid, using method J is (that be obtained commercially or as at above intermediate from the precursor specified Described in preparation) prepare following embodiment.
Embodiment 236
(8-is anti-(anti))-3-(5-{ (1R, 3R)-1-[2-(difluoro-methoxy) phenyl]-6-fluoro-3-hydroxyl-2,3-two Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-7-base } pyrimidine-2-base)-3-azabicyclo [3.2.1] octane-8-formic acid
By method G, prepare title compound (418mg, 85%) from intermediate 163 (501mg, 0.86mmol).LCMS (ES+)RT 1.08min,566.0(M+H)+。
Embodiment 237 method L
(1R, 3R or S)-1-[2-(difluoro-methoxy) phenyl] the fluoro-7-of-8-[4-(methyl sulphonyl) phenyl]-2,3-two Hydrogen-1H-pyrrolo-[1,2-a] benzimidazole-3-alcohol
In microwave container (20ml), by intermediate 164 (50mg, 121 μm ol), sodium carbonate (52mg, 484 μm ol), 4- (methyl sulphonyl) phenylboric acid (49mg, 242 μm ol) and double (diphenylphosphino) ferrocene-palladium chloride (II) two of 1,1'- Chloromethanes complex (20mg, 24 μm ol) mixes with DME (4mL) and water (1mL).Heat 15 minutes at 100 DEG C and be cooled to room After temperature, add water, and aqueous phase DCM (× 3) is extracted.By dried over sodium sulfate for the organic facies of merging, filter and in vacuum Middle concentration.By chromatography (SiO2, the EtOH of 0-10% solution in DCM) and purification residue.By residue by preparation Type HPLC (M2b) is further purified, and obtains title compound (42mg, 71%).LCMS[M 1b](ES+)RT 1.57min, 489.1(M+H)+。
Embodiment 238-239
Suitable borate or boric acid is used to prepare following embodiment from given initiation material by method L.
Embodiment 240
Suitable borate or boric acid is used to prepare embodiment 40 from given initiation material by method L.
Embodiment 241
2-(5-{4-[2-(difluoro-methoxy) phenyl]-8-fluoro-1,2,3,4-tetrahydrochysene pyrazine also [1,2-a] benzimidazole- 7-yl } pyrimidine-2-base) propane-2-alcohol
In room temperature, intermediate 165 (210mg, 369 μm ol) is dissolved in twoIn alkane (5mL), and add hydrogen chloride solution (1mL) TFA (0.5mL), it is subsequently added.After stirring 1h, mixture is stood 18h, and is heated to 60 DEG C of holding 1.5h.Add The TFA (0.5mL) of additional amount, and after 1.25h, mixture is cooled to room temperature, and adds EtOAc and saturated bicarbonate Sodium solution.After Xiang Fenliing, aqueous phase EtOAc is extracted 2 times.The organic phases washed with brine that will merge, dried over sodium sulfate, Filter and concentrate in a vacuum.By preparation HPLC (M2d) purification residue, obtain title compound (105mg, 61%). LCMS[M 1b](ES+)RT 1.31min,470.3(M+H)+。

Claims (25)

1. the compound of formula (I) or its N-oxide or its pharmaceutically acceptable salt or solvate or its glucosiduronic acid Derivant or its eutectic:
Wherein
N represents the integer equal to 0 or 1；
X and Z represents covalent bond independently；Or hetero atom；Or carbonyl, or S (O)-,-S (O)2-、-S(O)(N-Rd)、-NC(O)- Rd、-N(CO)-ORd、-NS(O)2RdOr-N (Rd)；Or the straight or branched C being optionally substituted1-4Alkylidene chain；
Y represents C3-7Cycloalkyl, aryl, C3-7Heterocyclylalkyl or heteroaryl, any one in described group can be optionally by one Individual or multiple substituent groups replace；
R1And R2Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy ,-OR independentlya、-SRa、- SORa、-SO2Ra、-SF5、-NRbRc、-NRcCORd、-NRcCO2Rd、-NHCONRbRc、-NRcSO2Re、-N(SO2Re)2、- NHSO2NRbRc、-CORd、-CO2Rd、-CONRbRc、-CON(ORa)Rb、-SO2NRbRcOr-S (O) (N-Rd)Ra；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C3-7Cycloalkyl, C4-7Cycloalkenyl group, C3-7Cycloalkyl (C1-6) alkyl, aryl, aryl (C1-6) alkyl, C3-7 Heterocyclylalkyl, C3-7Heterocyclylalkyl (C1-6) alkyl, C3-7Heterocycloalkenyl, C4-9Miscellaneous bicyclic alkyl, heteroaryl, heteroaryl (C1-6) alkane Base, (C3-7) Heterocyclylalkyl (C1-6) alkyl-aryl-group-, heteroaryl (C3-7) Heterocyclylalkyl-, (C3-7) cycloalkyl-heteroaryl-, (C3-7) cycloalkyl (C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl-heteroaryl-, (C3-7) Heterocyclylalkyl-heteroaryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-heteroaryl-, (C4-9) miscellaneous Bicyclic alkyl-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl-, any one in described group can be optionally by one Or multiple substituent group replaces；
R3And R4Represent hydrogen, halogen, cyano group, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy independently；Or-ORa、-SRa、- SORaOr-SO2Ra；Or the C being optionally substituted with one or more substituents1-6Alkyl；
R5aAnd R5bRepresent hydrogen, hydroxyl, halogen, trifluoromethyl or cyano group independently；Or-NRbRc、-NRcC(O)Rd、-(CO) NRcRd、-NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)Ra、-S(O)2(N-Rd)、-ORd、-C(O)- ORd、-O(CO)-Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heteroaryl, any one in described group can be appointed Selection of land is substituted with one or more substituents；Or R5aAnd R5bCarbonyl, thiocarbonyl or-C is represented together with the carbon being connected with them =N-OH；And
R6Represent hydrogen, hydroxyl, halogen, trifluoromethyl or cyano group；Or-NRbRc、-NRcC(O)Rd、-(CO)NRcRd、-NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)Ra、-S(O)2(N-Rd)、-ORd、-C(O)-ORdOr-O (CO)- Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heteroaryl, any one in described group can be optionally by one Or multiple substituent group replaces；Or R6Formed together with the carbon being connected with them with Y and be optionally substituted with one or more substituents C3-7Cycloalkyl or C3-7Heterocyclylalkyl；And
RaRepresent C1-6Alkyl, C3-7Cycloalkyl, C3-7Heterocyclylalkyl, aryl, aryl (C1-6) alkyl, heteroaryl or heteroaryl (C1-6) Alkyl, any one in described group can optionally be substituted with one or more substituents；
RbAnd RcRepresent hydrogen or trifluoromethyl independently；Or C1-6Alkyl, C3-7Cycloalkyl, C3-7Cycloalkyl (C1-6) alkyl, aryl, Aryl (C1-6) alkyl, C3-7Heterocyclylalkyl, C3-7Heterocyclylalkyl (C1-6) alkyl, heteroaryl or heteroaryl (C1-6) alkyl, described base Any one in group can optionally be substituted with one or more substituents；Or
RbAnd RcRepresent together with the nitrogen-atoms being connected with both of which azetidine-1-base, pyrrolidin-1-yl,Oxazolidine- 3-base, differentOxazolidine-2-base, Thiazolidine-3-base, isothiazolidine-2-base, piperidin-1-yl, morpholine-4-base, thiomorpholine-4- Base, piperazine-1-base, high piperidin-1-yl, high morpholine-4-base, homopiperazine-1-base, (imino group) (oxo) thiazan-4-base, (oxo) thiazan-4-base or (dioxo) thiazan-4-base, any one in described group can be optionally by one or many Individual substituent group replaces；
RdRepresent hydrogen；Or C1-6Alkyl, C3-7Cycloalkyl, aryl, C3-7Heterocyclylalkyl or heteroaryl, any one in described group can To be optionally substituted with one or more substituents；And
ReRepresent C1-6Alkyl, aryl or heteroaryl, any one in described group can be optionally by one or more substituent groups Replace.
The compound being the most such as defined in claim 1 or its N-oxide or its pharmaceutically acceptable salt or solvation Thing or its glucuronide or its eutectic, described formula (IIB) represents:
Wherein
R1Represent halogen or cyano group；Or C1-6Alkyl, C2-6Alkynyl, aryl, C3-7Heterocyclylalkyl, C3-7Heterocycloalkenyl, heteroaryl, (C3-7) Heterocyclylalkyl (C1-6) alkyl-aryl-group-, heteroaryl (C3-7) Heterocyclylalkyl-, (C3-7) cycloalkyl-heteroaryl-, (C3-7) ring Alkyl-(C1-6) alkyl-heteroaryl-, (C4-7) cycloalkenyl group-heteroaryl-, (C4-9) bicyclic alkyl-heteroaryl-, (C3-7) heterocycle alkane Base-heteroaryl-, (C3-7) Heterocyclylalkyl (C1-6) alkyl-heteroaryl-, (C3-7) heterocycloalkenyl-heteroaryl-, (C4-9) miscellaneous two cycloalkanes Base-heteroaryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl-, any one in described group can be the most one or more Substituent group replaces；
R2Represent hydrogen, halogen, cyano group, trifluoromethyl；Or the C being optionally substituted1-6Alkyl；
X represents oxygen atom or sulphur atom；-S (O) or-N-Rd；Or the straight or branched C being optionally substituted1-4Alkylidene chain；
R5aRepresent hydrogen, hydroxyl, halogen, cyano group or trifluoromethyl；Or-NRbRc、-NRcC(O)Rd、-(CO)NRcRd、-NHS(O)2Re、-S-Ra、-(SO)-Ra、-S(O)2Ra、-S(O)(N-Rd)、-S(O)2(N-Rd)、-ORa、-C(O)2RdOr-O (CO)-Rd-；Or C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl, heteroaryl, any one in described group can be the most one or more Substituent group replaces；And
R5bRepresent hydrogen, hydroxyl, halogen, cyano group or trifluoromethyl；Or C1-6Alkyl, any one in described group can be optionally It is substituted with one or more substituents；Or
R5aAnd R5bCarbonyl, thiocarbonyl or-C=N-OH is represented together with the carbon being connected with them；And
Y、Ra、Rb、RcAnd RdAs being defined in claim 1.
3. such as the compound claimed in claim 1 or in claim 2, wherein,
R1Represent aryl, (C3-7) heterocycloalkenyl-, heteroaryl, (C3-7) Heterocyclylalkyl-heteroaryl-, (C4-9) miscellaneous bicyclic alkyl-miscellaneous Aryl-or (C4-9) spiroheterocyclic alkyl-heteroaryl, any one in described group can be optionally by one or more substituent groups Replace.
4. such as the compound or its N-oxide that claim in claim 1 or in claim 2 or pharmaceutically may be used The salt accepted or its solvate or its glucuronide or its eutectic, described formula (IIC) represents:
V represents C-R12Or N；
R9Represent hydrogen, halogen, halo (C1-6) alkyl, cyano group, cyano group (C1-6) alkyl, nitro (C1-6) alkyl, C1-6Alkyl, trifluoro Methyl, trifluoroethyl, C2-6Thiazolinyl, hydroxyl, hydroxyl (C1-6) alkyl, C1-6Alkoxyl, trifluoro ethoxy, carboxyl (C3-7) cycloalkanes oxygen Base, C1-6Alkylthio group, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, oxo, amino, amino-(C1-6) alkyl, C1-6Alkyl amino, two (C1-6) alkyl amino, (C1-6) alkoxyl (C1-6) alkyl amino, N-[(C1-6) alkyl]-N-[hydroxyl (C1-6) alkyl] amino, (C2-6) alkyl-carbonyl-amino (C1-6) alkyl, C1-6Alkyl sulfonyl-amino, N-[(C1-6) alkyl]-N- [(C1-6) alkyl sulphonyl] amino, double [(C1-6) alkyl-sulfonyl base] amino, N-[(C1-6) alkyl]-N-[carboxyl (C1-6) alkane Base] amino, carboxyl (C3-7) cycloalkyl-amino, carboxyl (C3-7) cycloalkyl (C1-6) alkyl amino, formoxyl, C2-6Alkyl-carbonyl, (C2-6) alkyl-carbonyloxy base (C1-6) alkyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, morpholinyl (C1-6) alkoxy carbonyl, C2-6Alkoxy carbonyl-methylene, amino carbonyl, amino-sulfonyl, (C1-6) alkyl sulfide sulfoximide base, [(C1-6) alkyl] [N-(C1-6) alkyl] sulfur sulfoximide base；Or R9Represent (C3-7) cycloalkyl, (C3-7) cycloalkyl (C1-6) alkyl, (C4-7) cycloalkenyl group, (C4-9) bicyclic alkyl, (C3-7) Heterocyclylalkyl, (C3-7) heterocycloalkenyl, (C4-9) miscellaneous bicyclic alkyl, (C4-9) spiroheterocyclic alkyl or heteroaryl, any one in described group can optionally by one or Multiple substituent groups replace；Or R9Represent optionally substituted (C1-6) alkyl amino sulfonyl；
R10And R11Represent hydrogen, halogen, cyano group, trifluoromethyl, hydroxyl ,-NR independentlybRcOr-ORa；Or C1-6Alkyl, C1-6Alkyl Sulfonyl；
R12Represent hydrogen, halogen or C1-6Alkyl；And
X、R2、R5a、R5b、Ra、RbAnd RcAs being defined in claim 1.
The compound being the most such as defined in claim 4 or its N-oxide or its pharmaceutically acceptable salt or its solvent Compound or its glucuronide or its eutectic, described formula (IID), (IIE), (IIF), (IIG), (IIH), (IIJ), (IIK), (IIL), (IIM) or (IIN) represents:
Wherein
T representative-CH2-or-CH2-CH2-；
U represents C (O) or S (O2)；
W represents O, S, S (O), S (O)2、S(O)(N-Rd)、N(R14) or C (R15)(R16)；
-M-representative-CH2-、-CH2CH2-or-CH2-W-CH2；
Q represents C (R15)(R16)；
R13Represent hydrogen, cyano group, halogen, halo (C1-6) alkyl, hydroxyl, C1-6Alkoxyl, C1-6Alkylthio group, C1-6Alkyl sulfenyl Base, C1-6Alkyl sulphonyl, amino, C1-6Alkyl amino, two (C1-6) alkyl-amino, (C2-6) alkyl-carbonyl-amino, (C2-6) alkane Base carbonylamino (C1-6) alkyl, (C1-6) alkyl-sulfonylamino or (C1-6) alkyl sulfonyl-amino (C1-6) alkyl；
R14Represent hydrogen, cyano group (C1-6) alkyl, C1-6Alkyl, trifluoromethyl, trifluoro ethyl, C1-6Alkyl sulphonyl, (C1-6) alkyl Sulfonyl (C1-6) alkyl, formoxyl, C2-6Alkyl-carbonyl, carboxyl, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxyl Carbonyl (C1-6) alkyl, carboxylic acid isostere or prodrug moiety Ω ,-(C1-6) alkyl-Ω, amino carbonyl, C1-6Alkyl amino carbonyl Base, two (C1-6) alkyl amino-carbonyl, amino-sulfonyl or two (C1-6) alkyl amino-sulfonyl；
R15Represent hydrogen, halogen, cyano group, hydroxyl, hydroxyl (C1-6) alkyl, C1-6Alkyl sulphonyl, formoxyl, C2-6Alkyl-carbonyl, carboxylic Base, carboxyl (C1-6) alkyl, C2-6Alkoxy carbonyl, C2-6Alkoxy carbonyl (C1-6) alkyl, amino-sulfonyl, (C1-6) alkyl-sulfur Sulfoximide base, [(C1-6) alkyl] [N-(C1-6) alkyl] sulfur sulfoximide base, carboxylic acid isostere or prodrug moiety Ω or- (C1-6) alkyl-Ω；With
R16Represent hydrogen, halogen, C1-6Alkyl, C3-7Cycloalkyl, trifluoromethyl, hydroxyl, hydroxyl-(C1-6) alkyl, C1-6Alkoxyl, ammonia Base or carboxyl；
X、R2、R5aAnd R5bAs being defined in claim 1；And
V、R10And R11As being defined in claim 4.
6. as compound the most claimed or its N-oxide or its pharmaceutically acceptable salt or its Solvate or its glucuronide or its eutectic, described formula (IIP) represents:
Wherein
X、Y、R2、R5aAnd R5bAs being defined in claim 2；And
R9、R10And R11As being defined in claim 4.
7. such as compound claimed in any one in aforementioned claim, wherein
R5aRepresent hydrogen or hydroxyl.
8. such as compound claimed in any one in aforementioned claim, wherein R5bRepresent hydrogen or methyl.
9. as compound the most claimed or its N-oxide or its pharmaceutically acceptable salt or its Solvate or its glucuronide or its eutectic, described formula (IIR) represents:
Wherein
Z represents hetero atom；Or-S (O) ,-S (O)2、-S(O)(N-Rd)、-NC(O)Rd、-N(CO)-ORd、-NS(O)2Rd、-N(Rd)； Or the straight or branched C being optionally substituted1-4Alkylidene chain；And
Y is such as defined in claim 1；
R1As being defined in claim 3；And
R2As being defined in claim 2.
10. as compound the most claimed or its N-oxide or its pharmaceutically acceptable salt or its Solvate or its glucuronide or its eutectic, described formula (IIS) represents:
Wherein
Z is such as defined in claim 9；
Y is such as defined in claim 1；
R2As being defined in claim 2；And
V、R9、R10And R11As being defined in claim 4.
11. such as compounds the most claimed or its N-oxide or its pharmaceutically acceptable salt or its Solvate or its glucuronide or its eutectic, described formula (IIQ) represents:
Wherein
Y is such as defined in claim 1；
R1As being defined in claim 3；And
R2As being defined in claim 2.
Compound claimed in 12. such as any one in claim 4,6 or 10, wherein,
R9Represent hydrogen, hydroxyl, C1-6Alkyl, (hydroxyl) C1-6Alkyl, C1-6Alkoxyl, C2-6Alkyl-carbonyl, C1-6Alkyl sulphonyl, (C1-6) alkyl sulphonyl (C1-6) alkyl, (C1-6) alkyl sulfide sulfoximide base, oxo or carboxyl；Or R9Represent (C3-7) cycloalkyl, (C3-7) Heterocyclylalkyl or (C4-9) miscellaneous bicyclic alkyl；Or cyano group (C1-6) alkyl, (C3-7) naphthene sulfamide base or (C1-6) alkyl ammonia Base sulfonyl, any one in described group can optionally be substituted with one or more substituents.
Compound claimed in 13. such as any one in aforementioned claim, wherein X represents methylene.
Compound claimed in 14. such as any one in aforementioned claim, wherein Y represents the virtue being optionally substituted Base.
15. such as the compound claimed in claims 9 or in claim 10, wherein Z represents oxygen ,-NH ,-NCH3、- N-(SO2)-CH3、-N-(CO)-CH3Or-N-(CO)-O-CH3。
Compound claimed in 16. such as any one in aforementioned claim, wherein R2Represent hydrogen or halogen.
17. such as disclosed compound clearly in any one embodiment of the application.
18. with in the treatment such as the compound being defined in claim 1 or its N-oxide or it is pharmaceutically acceptable Salt or its solvate or its glucuronide or its eutectic.
19. for treatment and/or prevention be instructed to use TNF α function regulator obstacle as being defined in claim 1 The compound of formula (I) or its N-oxide or its pharmaceutically acceptable salt or its solvate or its glucosiduronic acid derive Thing or its eutectic.
20. are used for treatment and/or preventing inflammatory or autoimmune disorders, neurological or neural degeneration obstacle, pain or wound Evil susceptibility obstacle, cardiovascular disorder, dysbolismus, eye disorder or oncology's obstacle as claimed in claim 1 The compound of formula (I) or its N-oxide or its pharmaceutically acceptable salt.
21. pharmaceutical compositions, its compound comprising formula (I) as being defined in claim 1 or its N-oxide or its Pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
The compound of 22. formulas being such as defined in claim 1 (I) or its N-oxide or its pharmaceutically acceptable salt or Solvate or its glucuronide or its eutectic for preparing the purposes of medicine, described medicine for treatment and/or Prevention is instructed to use the obstacle of TNF α function regulator.
The compound of 23. formulas being such as defined in claim 1 (I) or its N-oxide or its pharmaceutically acceptable salt or Solvate or its glucuronide or its eutectic for preparing the purposes of medicine, described medicine for treatment and/or Preventing inflammatory or autoimmune disorders, neurological or neural degeneration obstacle, pain or nociception sexual disorders, cardiovascular barrier Hinder, dysbolismus, eye disorder or oncology's obstacle.
24. for treatment and/or prevent the method being instructed to use the obstacle of TNF α function regulator, and described method includes to needing The patient wanting this treatment use effective dose as the compound of formula (I) being defined in claim 1 or its N-oxide, Or its pharmaceutically acceptable salt or solvate or its glucuronide or its eutectic.
25. are used for treatment and/or preventing inflammatory or autoimmune disorders, neurological or neural degeneration obstacle, pain or wound Evil susceptibility obstacle, cardiovascular disorder, dysbolismus, eye disorder or the method for oncology's obstacle, described method includes to needs The patient of this treatment use effective dose such as the compound of formula (I) being defined in claim 1 or its N-oxide or Its pharmaceutically acceptable salt or solvate or its glucuronide or its eutectic.
CN201480067052.9A 2013-12-09 2014-12-08 Fused tricyclic benzimidizole derivatives as TNF active regulators Expired - Fee Related CN105814048B (en)

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